Isochroman compounds for treatment of CNS disorders

ABSTRACT

This invention relates to compounds of formula (I) 
                         
where R 1  to R 12 , —W—V—, —X—Y—, p and n have the values defined in claim  1 , their preparation and use as pharmaceuticals for the treatment of central nervous system disorders, such as depression, bipolar disorder, and anxiety.

This invention relates to novel compounds, their preparation and use aspharmaceuticals.

Certain isochroman compounds useful as antipsychotics and in thetreatment of disorders of the central nervous system, are disclosed inWO 95/18118 and WO 97/02259.

The compounds of the invention are of the following general formula:

in which

-   R¹ is any one of    -   —CN, —CONR¹³R¹⁴, —SO₂NR¹³R¹⁴, —(CH₂)_(t)—R^(21,)

-   —R²¹ is any one of

where R¹³, R¹⁴, R²² and R²³ are each hydrogen or C₁₋₆ alkyl, or R¹³ andR¹⁴ taken together with the nitrogen atom to which they are attachedform a morpholino, pyrrolidino or piperidinyl ring optionallysubstituted with one or two C₁₋₆ alkyl groups.

R¹³′ and R²⁴ are each independently selected from hydrogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, nitro,amino, C₁₋₆ acylamino, C₁₋₆ alkylthio, phenyl or phenoxy.

A is O or S

t is 0, 1 or 2,

r is 0, 1, 2 or 3,

v is 0,1 or 2;

-   R² is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or halo;-   R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each hydrogen or C₁₋₆ alkyl;-   R⁹, R¹⁰, R¹¹ and R¹² are each hydrogen, C₁₋₆ alkyl or    —(CH₂)_(q)—OR²⁰, wherein R²⁰ is C₁₋₆ alkyl;-   n is 1 or 2;-   p is 0, 1 or 2;-   q is 1 or 2;

is any one of

-   R²⁵ is hydrogen or C₁₋₆ alkyl;-   —X—Y— is

where Z is any one of

in which -T- is —CH₂—, —O—, —S—, —C(O)— or —CH═CH—, m and s are each 0or 1,

R¹⁵, R¹⁶ and R¹⁹ are each hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ alkoxy,carboxy-C₁₋₆ alkyl, cyano, halogen, trifluoromethyl, trifluoromethoxy,nitro, amino, C₁-C₆ acylamino or C₁-C₆ alkylthio and R¹⁷ and R¹⁸ areeach hydrogen or C₁₋₆ alkyl,

Q is hydrogen, halo, nitrile, carboxy-C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyl orC₁₋₆ alkoxy; and pharmaceutically acceptable salts thereof; providedthat:

-   a) when -T- is —CH₂—, —O—, —S— or —C(O)—, then (m+s) is 1 or 2, and-   b) when Z is (i)_(a), (ii)_(a), (iii)_(a), (iv), (v)_(a), (vi),    (vii), (viii)_(a), (x)_(a), (xi)_(a), (xii)_(a), (x)_(b), (xi)_(b)    or (xiii), then R¹ is —(CH₂)_(t)—R²¹.

The compounds of the invention and their pharmaceutically acceptablesalts are indicated for use as a pharmaceutical. Particularly thecompounds of the invention and their pharmaceutically acceptable saltsare indicated for use in the treatment of disorders of the centralnervous system.

Accordingly the present invention also includes the use of a compound offormula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of a disorder of thecentral nervous system in mammals. The present invention also includes amethod of treating an animal, including a human, suffering from orsusceptible to a disorder of the central nervous system, which comprisesadministering a therapeutically effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof.

In the above formula (I), a C₁₋₆ alkyl group can be branched orunbranched and, for example, includes methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl and hexyl, and is preferably methyl orethyl, and especially methyl. A C₁₋₆ alkoxy group is one such alkylgroup linked to a ring through an oxygen atom, and is preferably methoxyor ethoxy, and especially methoxy. A halo group is fluoro, chloro orbromo, and especially fluoro. A (C₁-C₆)alkylthio is an alkyl grouplinked to a sulphur atom, where the alkyl group is as defined above. A(C₁-C₆)alkylthio group includes for example thiomethyl or thioethyl. AC₁-C₆ acylamino group is an alkyl group linked to an amide group, wherethe alkyl is as defined above, and is preferably of the formulaR^(IV)—NH—CO— where R^(IV) is C₁-C₅ alkyl. A C₁-C₆ acylamino groupincludes for example acetamide.

Particular embodiments of the present invention include the followinggroups of compounds of formula (I) wherein:

-   1. R¹ is —CONR¹³R¹⁴ and Z is independently selected from (xxi),    (xxi), (xxiv) or (xxv);-   2. Z is (xxi), T is —CH₂— and (m+s) is 1;-   3. Z is (xxi), T is —O— and m is 1 and s is 1;-   4. Z is (xxi), T is —S— and m is 1 and s is 1;-   5. Z is (xxi), T is —CH═CH— and both m and s are 0;-   6. Z is (xxi), T is —C(O)— and both m and s are 0;-   7. R³ to R⁸ are each C₁₋₆ alkyl;-   8. n is 1 or 2, preferably n is 2;-   9. n is 1;-   10. p is 1;-   11. p is 2;-   12. each of R¹³ and R¹⁴ is hydrogen; or-   13. one of R⁹, R¹⁰, R¹¹ and R¹² is C₁₋₆ alkyl, preferably methyl or    ethyl, and each of the remainder of R⁹, R¹⁰, R¹¹ or R¹² is hydrogen.

When n is 2 it will be appreciated that the values of R³ and R⁴ in therepeated units can be different.

In a particular embodiment of the present invention, R¹ is—(CH₂)_(t)—R²¹.

In another particular embodiment of the present invention, Z is (xxi),(xxii), (xxiii), (xxiv) or (xxv).

In a further embodiment of the present invention, R¹ is —(CH₂)_(t)—R²¹and Z is (xxi), (xxii), (xxiii) or (xxv).

Any of the groups of compounds of formula (I) above may be combined withany other group or groups to define further particular embodiments ofthe present invention.

In a preferred embodiment, R¹ is CONR¹³R¹⁴ and Z is (xxi). In saidembodiment:

-   -   when -T- is —O—, preferably m is 1 and s is 1;    -   when -T- is —S—, preferably m is 1 and s is 1;    -   when -T- is —CH₂—, (m+s) is preferably 1;    -   when -T- is —C(O)—, (m+s) is preferably 1; and    -   when -T- is —CH═CH—, (m+s) is preferably 0;

In another preferred embodiment, R¹ is —(CH₂)_(t)—R²¹ and Z is any oneof (xxi), (i)a and (xii)a, especially (xxi) or (i)a.

In a preferred group of compounds of formula (I) according to thepresent invention, R¹ is —CONR¹³R¹⁴. More preferably, R¹ is —CONR¹³R¹⁴where R¹³ and R¹⁴ are each hydrogen or C₁₋₆ alkyl, especially hydrogen.

In another preferred group of compounds of formula (I) according to thepresent invention, R¹ is —(CH₂)_(t)—R²¹. More preferably, R¹ is—(CH₂)_(t)—R²¹ where t is O or 1. In the group —(CH₂)_(t)—R²¹, —R²¹ maybe any of the values defined above and:

-   -   R¹³ is preferably hydrogen or C₁-C₆ alkyl, especially hydrogen;    -   R¹⁴ is preferably hydrogen or C₁-C₆ alkyl, especially hydrogen;    -   R²⁴ is preferably hydrogen or C₁-C₆ alkyl, especially hydrogen;        or methyl;    -   R²² is preferably hydrogen or C₁-C₆ alkyl, especially hydrogen;        or methyl;        Preferred groups of compounds of formula (I) according to the        present invention, where R¹ is —(CH₂)_(t)—R²¹, include the        following:

-   a) —R²¹ is

-   -   t is 1 and R¹⁴ and R¹³ are each hydrogen;

-   b) —R²¹ is

-   -   t is O and R¹⁴ and R¹³ are each hydrogen;

-   c) —R²¹ is

-   -   t is 1 and R¹³ and R²² are each hydrogen;

-   d) —R²¹ is

-   -   t is 1, R¹³ is H and R²² is methyl;

-   e) —R²¹ is

-   -   t is 1, R¹³ is H and R²² is methyl;

-   f) —R²¹ is

-   -   t is 1 and v is 0;

-   g) —R²¹ is

-   -   t is 1 and r is 1;

-   h) —R²¹ is

-   -   t is 0, R²² is H and v is 0;

-   i ) —R²¹ is

-   -   t is O, v is 1 and A is S;

-   j) —R²¹ is

-   -   t is 0, v is 1 and A is O;

-   k) —R²¹ is

-   -   t is 0 and r is 1;

-   l) —R²¹ is

-   -   t is 0 and r is 0;

-   m) —R²¹ is

-   -   t is 0 and R²⁴ is H;

-   n) —R²¹ is

-   -   t is 1 and R²⁴ is H;

-   o) —R²¹ is

-   -   t is 1 and R²⁴ is H;

-   p) —R²¹ is

and t is 0;

-   q) —R²¹ is

-   -   t is 0 and v is 0;

-   r) —R²¹ is

-   -   t is 0 and R²⁴ is H;

-   s) —R²¹ is

-   -   t is 0 and R²⁴ is H;

-   t) —R²¹ is

-   -   t is 0 and R²⁴ is H;

-   u) —R²¹ is

-   -   t is 0 and v is 0;

-   v) —R²¹ is

-   -   t is 0, v is 0 and R²² is methyl;

-   w) —R²¹ is

-   -   t is 0 and R²⁴ is hydrogen.

In the compounds of the present invention, R² is preferably hydrogen orC₁₋₆ alkyl, especially hydrogen.

Each of R³, R⁴, R⁵, R⁶, R⁷ and R⁸ is preferably hydrogen.

When one or each of R¹¹ and R¹² is C₁-C₆ alkyl or —(CH₂)_(q)—OR²⁰, R⁹and R¹⁰ are both preferably hydrogen.

When one or each of R⁹ and R¹⁰ is C₁-C₆ alkyl or —(CH₂)_(q)—OR²⁰, R¹¹andR¹² are both preferably hydrogen.

In a preferred embodiment, R⁹, R¹⁰, R¹¹ and R¹² are each hydrogen. Inanother preferred embodiment, one of R¹¹ and R¹² is methyl and the otheris hydrogen, and R⁹ and R¹⁰ are both hydrogen.

In the compounds of the present invention, p is preferably 1 or 2.

In a preferred embodiment of the present invention,

In said embodiment preferably R²⁵ is hydrogen.

In another preferred embodiment of the present invention, —X—Y— is

In another preferred embodiment, —X—Y— is

In said invention Q is preferably hydrogen and more preferably R⁹, R¹⁰,R¹¹ and R¹² are hydrogen.

In further preferred embodiments, Z is (xxi); Z is (xxii); Z is (xxiii);Z is (xxiv), Z is (xxv); Z is (i)a; Z is (xii)a. Especially preferredcompounds are those in which Z is (xxi); Z is (i)a; Z is (xii)a. When Zis (i)_(a), preferably one of R¹⁵ and R¹⁶ is —CN and the other ishydrogen. When Z is (xii)_(a), preferably one of R¹⁵ and R¹⁶ is —F or—CN, and the other is hydrogen, and R¹⁹ is hydrogen.

When Z is (xxi), preferably m+s is 1 or 2.

In a preferred embodiment of the present invention, R¹ is —(CH₂)_(t)—R²¹and Z is (xii)_(a), wherein preferably one of R¹⁵ and R¹⁶ is —F or —CNand the other is hydrogen, and preferably R¹⁹ is hydrogen.

In another preferred embodiment of the present invention, R¹ is—(CH₂)_(t)—R²¹ and Z is (xxi), wherein -T- is preferably —CH₂— and (m+s)is preferably 1.

In yet another preferred embodiment of the present invention, R¹ is—(CH₂)_(t)—R²¹ and Z is (i)a, wherein preferably one of R¹⁵ and R¹⁶ is—CN, and the other is hydrogen.

Any of the preferred groups herein may be combined with any otherpreferred group or groups to define further preferred compounds.

Preferred compounds of formula (I) of the present invention includecompounds of formulae:

wherein R¹, R², R⁵ to R¹⁰ and Z have the values defined for formula Iabove, with the provisos for formula I; Particularly preferred compoundsof formula (I″) include groups of compounds wherein R⁵ to R⁸ arehydrogen; or wherein R² is hydrogen; or wherein R¹ is —CONR¹³R¹⁴,wherein preferably R¹³ and R¹⁴ are hydrogen; or wherein Z is (xxi)wherein preferably -T- is —CH₂— and (m+s) is 1; or wherein one of R⁹,R¹⁰, R¹¹ and R¹² is C₁₋₆ alkyl, preferably methyl or ethyl and each ofthe remainder R⁹, R¹⁰, R¹¹ and R¹² is hydrogen. Particularly preferredcompounds of the invention include compounds of formula (I″) abovewherein R⁵ to R⁸ are hydrogen, R² is hydrogen, R¹ is —CONR¹³R¹⁴, whereinpreferably R¹³ and R¹⁴ are hydrogen, Z is (xxi), wherein preferably -T-is —CH₂— and (m+s) is 1 and one of R⁹, R¹⁰, R¹¹ and R¹² is C₁₋₆ alkyl,preferably methyl or ethyl and each of the remainder R⁹, R¹⁰, R¹¹ andR¹² is hydrogen;

wherein R¹, R², R⁵ to R¹⁰ and Z have the values defined for formula Iabove, with the provisos for formula I; Particularly preferred compoundsof formula (I′″) include groups of compounds wherein R⁵ to R⁸ arehydrogen; or wherein R² is hydrogen; or wherein R¹ is —CONR¹³R¹⁴,wherein preferably R¹³ and R¹⁴ are hydrogen; or wherein Z is (xxi)wherein preferably -T- is —CH₂— and (m+s) is 1; or wherein one of R⁹,R¹⁰, R¹¹ and R¹² is C₁₋₆ alkyl, preferably methyl or ethyl and each ofthe remainder R⁹, R¹⁰, R¹¹ and R¹² is hydrogen. Particularly preferredcompounds of the invention include compounds of formula (I′″) abovewherein R⁵ to R⁸ are hydrogen, R² is hydrogen, R¹ is —CONR¹³R¹⁴, whereinpreferably R¹³ and R¹⁴ are hydrogen, Z is (xxi), wherein preferably -T-is —CH₂— and (m+s) is 1 and one of R⁹, R¹⁰, R¹¹ and R¹² is C₁₋₆ alkyl,preferably methyl or ethyl and each of the remainder R⁹, R¹⁰, R¹¹ andR¹² is hydrogen; and

wherein R¹, R², R⁵ to R¹⁰, Q and Z have the values defined for formula Iabove, with the provisos for formula I; Particularly preferred compoundsof formula (I^(iv)) include groups of compounds wherein R⁵ to R⁸ arehydrogen; or wherein R² is hydrogen; or wherein Q is hydrogen; orwherein one of R⁹, R¹⁰, R¹¹ and R¹² is C₁₋₆ alkyl, preferably methyl orethyl and each of the remainder R⁹, R¹⁰, R¹¹ and R¹² is hydrogen.Particularly preferred compounds of the invention include compounds offormula (I^(iv)) above wherein R⁵ to R⁸ are hydrogen, R² is hydrogen, Qis hydrogen and one of R⁹, R¹⁰, R¹¹ and R¹² is C₁₋₆ alkyl, preferablymethyl or ethyl and each of the remainder R⁹, R¹⁰, R¹¹ and R¹² ishydrogen.

Particularly preferred compounds of the present invention of formula(I′):

wherein

Each of R¹³ and R¹⁴ is H or C₁-C₆ alkyl, preferably hydrogen;

Each of R⁵, R⁶, R⁷ and R⁸ is H or C₁-C₆ alkyl, preferably hydrogen;

One or both of R¹¹ and R¹² is C₁-C₆ alkyl, preferably methyl or ethyland especially methyl; preferably one of R¹¹ and R¹² is C₁-C₆ alkyl,preferably methyl or ethyl and especially methyl and the other ishydrogen;

Each of R⁹ and R¹⁰ is hydrogen, C₁-C₆ alkyl, preferably methyl orhydrogen and especially hydrogen. —X— is —CH— or —N—, especially —N—;

T is —CH₂—, —O—, —S—, —C(O)— or —CH═CH—, especially —CH₂— provided thatwhen T is —CH₂—, —O—, —S— or —C(O)—, m+s is 1 or 2, and each of m and sis 0 or 1; and when T is —CH₂—, m+s is especially 1.

Particularly preferred embodiment of the invention includes compounds offormula (I) selected from:

-   (1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide,-   (1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-ethylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide,-   (1S)-1-{2-[(2S)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-ethylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide,-   (1S)-1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-1H-1,4-diazepin-1-yl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide,-   (1S)-1-{2-[(2R)-4-(5-Acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide,-   (1S)-1-{2-[(2R)-2-Methyl-4-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide,-   (1S)-1-{2-[(2R)-2-Methyl-4-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide,-   (1S)-1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)-1-piperidinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide,-   (1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-1,3-dihydro-2-benzofuran-5-carboxamide,-   (1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-1,3-dihydro-2-benzofuran-5-carboxamide,-   1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-1H-1,4-diazepin-1-yl]ethyl}-1,3-dihydro-2-benzofuran-5-carboxamide,-   1-({2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methanamine,-   1-({2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methylformamide,-   N-[((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]acetamide,-   N-[((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]methanesulfonamide,-   5-[(3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl)piperazinyl]-2-naphthonitrile,-   3-[((1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]-1,3-oxazolidin-2-one,-   3-[(3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl)-piperazinyl]-1-benzothiophene-6-carbonitrile,-   1-[((1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]-2-pyrrolidinone,-   3-[(3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-1-pyrrolidinyl)methyl]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl)piperazinyl]-1-benzothiophene-6-carbonitrile,-   (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(1S)-6-(1H-imidazol-1-ylmethyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-2-methylpiperazine,-   3-((3R)-4-{2-[(1S)-6-(1H-Imidazol-1-ylmethyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-3-methyl-piperazinyl)-1-benzothiophene-6-carbonitrile,-   3-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-pyrazol-1-ylmethyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile,-   (1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine,-   3-((1S)-1-{2-[(2R)-4-(6-Cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one,-   3-((1S)-1-{2-[(2R)-4-(1,2-dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one,-   3-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one,-   1-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-pyrrolidinone,-   1-((1S)-1-{2-[(2R)-4-(6-Cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-pyrrolidinone,-   1-((1S)-1-{2-[(2R)-4-(6-cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-pyrrolidinone,-   1-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-azetidinone,-   1-((1S)-1-{2-[(2R)-4-(6-cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-azetidinone,-   (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(1S)-6-(1,1-dioxido-2-isothiazolidinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-2-methylpiperazine,-   1-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-imidazolidinone,-   1-((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-imidazolidinone,-   1-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-3-methyl-2-imidazolidinone,-   3-((3R)-3-Methyl-4-{2-[(1S)-6-(4-thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile,-   3-((3R)-3-Methyl-4-{2-[(1S)-6-(4-morpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile,-   (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine,-   3-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile,-   (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(1S)-6-(1H-imidazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-2-methylpiperazine,-   3-((3R)-4-{2-[(1S)-6-(1H-Imidazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-3-methylpiperazinyl)-1-benzothiophene-6-carbonitrile,-   (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine,-   (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(1H-1,2,3-triazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine,-   3-((3R)-3-Methyl-4-{2-[(1S)-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile,-   3-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-1,2,3-triazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile,-   (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(1H-1,2,4-triazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine,-   3-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-1,2,4-triazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile,-   1-((1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2(1H)-pyridinone,    and-   3-((3R)-3-Methyl-4-{2-[(1S)-6-(2-oxo-1(2H)-pyridinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile    and pharmaceutically acceptable salts thereof.

An especially preferred compound of formula (I) is(1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamideand pharmaceutically acceptable salts thereof.

As indicated above, it is, of course, possible to prepare salts of thecompounds of the invention and such salts are included in the invention.Acid addition salts are preferably the pharmaceutically acceptable,non-toxic addition salts with suitable acids, such as those withinorganic acids, for example hydrochloric, hydrobromic, nitric,sulphuric or phosphoric acids, or with organic acids, such as organiccarboxylic acids, for example glycollic, maleic, hydroxymaleic, fumaric,malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organicsulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic,naphthalene-2-sulphonic or bisethane sulphonic acids. The fumarate is amost preferred salt.

In addition to the pharmaceutically acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of compounds or in the preparation of compounds or in thepreparation of other, for example pharmaceutically acceptable acidaddition salts, or are useful for identification, characterisation orpurification.

It will be appreciated that the compounds of the invention can containone or more asymmetric carbon atoms which gives rise to isomers. Thecompounds are normally prepared as racemic mixtures, but individualisomers can be isolated by conventional techniques if so desired. Suchracemic mixtures and individual optical isomers form part of the presentinvention, the compounds being employed as racemates or inenantiomerically pure form.

Preferred compounds of the invention are those of formula:

wherein

—X—Y—, R¹ to R¹², n and p have the values defined for formula I above,and —W— is —CH₂—, —O—, or —S—, with the proviso's as for formula Iabove.

Compounds of formula Ia can contain more asymmetric carbons. For examplewhen the R¹¹ and R¹² groups are different, this gives rise to furtherisomers, such as compounds of formula (Ib) and (Ic):

wherein all of the values —X—Y—, R¹ to R¹², n and p are as defined informula (I) above, and —W— is —CH₂—, —O— or —S—, with the proviso'stherein. Said isomers are also an aspect of the present invention.

Compounds of formula (Ib) above, wherein the group R¹¹ takes priorityover R¹² according to the Cahn-Ingold-Prelog sequence rules as describedin J. March, Fourth Edition, Chapter 4, page 109, and wherein thereforethe configuration of the carbon to which R¹¹ and R¹² are attached is R,are preferred. Particularly preferred compounds are those of formula(Ib) wherein R⁹, R¹⁰ and R¹² are hydrogen and R¹¹ is C₁₋₆ alkyl.

In the same way, when the R⁹ and R¹⁰ groups are different in compoundsof formula Ia, this also gives rise to isomers, such as compounds offormula (Id) and (Ie):

wherein all of the values —X—Y—, R¹ to R¹², n and p have the valuesdefined for formula I above, and —W— is —CH₂—, —O—, or —S— with theproviso's as for formula I. Said isomers are also an aspect of theinvention.

Compounds of formula (Id) above, wherein the group R⁹ takes priorityover R¹⁰ according to the Cahn-Ingold-Prelog sequence rules as describedin J. March, Fourth Edition, Chapter 4, page 109, and wherein thereforethe configuration of the carbon to which R⁹ and R¹⁰ are attached is R,are preferred. Particularly preferred compounds are those of formula(Id) wherein R⁹ is C₁₋₆ alkyl and R¹⁰, R¹¹ and R¹² are hydrogen.

The preferred stereochemistry detailed above applies also the compoundsof the present invention of formulae (I′), (I″), (I′″) and (I^(iv)).

The compounds of the invention can be produced by reacting a compoundhaving the formula:

where L is a leaving group, with a compound of the formula:

where the substituents have the values defined for formula (I) above.

The reaction is preferably carried out in the presence of a base such aspotassium carbonate, in an organic solvent such as a polar aproticsolvent, for example, acetonitrile, at a temperature of from 20° C. to100° C. Examples of suitable leaving groups are mesylate, tosylate,triflate, chloride, bromide and iodide, especially bromide and iodide.

Intermediate compounds of formula (III) can, for example, be preparedfrom the corresponding alcohols of the formula:

using standard methods known in the literature such as the ones shown inMarch, Advanced Organic Chemistry, Fourth Edition, for example themethods mentioned on pages 353 and 354.

Compounds of formula (IV) can be prepared by a variety of methods wellknown in the art. Substituted3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indoles, fluorosubstituted-3-(4-piperidinyl)-1H-indoles and(3R)-6-fluoro-3-(3-pyrrolidinyl)-1H-indole may be prepared using methodsdescribed in European patent application EP-A 0897921 and WO patentapplications WO 99/58525 and WO 00/02341. Substituted and unsubstituted4-(1-naphthyl)-1,2,3,6-tetrahydropyridines and 4-(1-naphthyl)piperidinesmay be prepared using methods described in U.S. Pat. Nos. 5,472,966,5,250,544, and 5,292,711. Substituted and unsubstituted1-(1-naphthyl)piperazines may be prepared using methods described inU.S. Pat. No. 5,166,156. (2R,4S)-2-methyl-4-(2-naphthyl)piperidine wasprepared using methods referred to in Med. Chem. Res. (1997), 7(4),207-218. Substituted and unsubstituted4-(1-benzopyran-3-yl)-1,2,3,6-tetrahydropyridines and4-(1-benzopyran-3-yl)piperidines may be prepared using methods describedin EP-A 0466585 or in Japanese patent JP 2000086603.6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1,2-benzisoxazole may beprepared by methods based on U.S. Pat. No. 3,678,062. Substituted andunsubstituted 6-fluoro-1-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indazolesmay be prepared by methods described in EP-A 0135781.4-(Thieno[3,2-b]pyrrol-6-yl)-1,2,3,6-tetrahydropyridine may be preparedby methods found in Heterocycl. Commun. (1999), 5(4) 305-310.Substituted and unsubstituted4-(1-benzothieny-7-yl)-1,2,3,6-tetrahydropyridines and4-(4-fluoro-1-benzopyran-7-yl)-1,2,3,6-tetrahydro-pyridine may beprepared using methods described in WO 00/00198. 6-Substituted2-[3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonates may be madeby procedures described in WO 95/18118.5-Methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole may be obtainedfrom Tocris Cookson. 3-[2-(4-piperidinyl)ethyl]-1H-indoles may beprepared using methods described in J. Med. Chem. 1993, 36(15), 2242 andJ. Med. Chem, 36(9) 1194.

Compounds of formula (IV) wherein R¹⁰ is —CH₂—OR²⁰ and X—Y— is

can be prepared as described in the synthetic scheme below:

In the above scheme, the nitrogen atoms are protected with a suitableprotecting group such as N-tert-butoxycarbonyl (BOC) or any othersuitable group using methods described in Greene and Wuts, ProtectingGroups in Organic Synthesis, 3rd. Ed., John Wiley & Sons, followed byreduction of the acid moiety to the alcohol, alkylation of said alcoholand deprotection of the nitrogen atoms.

The unprotected piperidine is then reacted with a compound of formulaZ-L^(iii) in the presence of a palladium catalyst such as palladiumacetate, BINAP ((R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and abase such as Caesium carbonate.

The nitrogen groups can for example be protected with a BOC group usingdi-tert-butyl dicarbonate in the presence of a base such as sodiumhydroxide in an organic solvent such as ethanol.

The reduction is preferably carried out in the presence of a reducingagent such as borane dimethyl sulfide in a organic solvent such as THFat a temperature ranging from 0° C. to room temperature.

The alkylation reaction is preferably carried out in an organic solventsuch as DMF, in the presence of a base such as sodium hydride and analkylating agent such as iodomethane (for compounds where R²⁰ ismethyl).

Compounds of formula (V) wherein R⁷ and R⁸ are hydrogen can, forexample, be prepared from the appropriate esters of the formula:

where R is C₁₋₆ alkyl. Such esters can be reduced in the presence of areducing agent such as lithium borohydride or lithium aluminium hydridein a suitable organic solvent such as tetrahydrofuran (THF).

Compounds of formula (V) wherein R¹ is —CONR¹³R¹⁴ can be prepared fromthe appropriate halo-substituted alcohols of the formula:

where R′ is a halo group, such as chloro, bromo or iodo. Such alcoholsare prepared using the same conditions as shown above. Then the alcoholis protected using a suitable protecting group as shown in Greene andWuts, Protecting Groups in Organic Synthesis, 3rd. Ed., John Wiley &Sons. Preferred protecting groups are silyloxy protecting groups such asfor example tertbutyldimethylsilyl group.

The halogen is then converted to the corresponding carboxamido group(—CONR¹³R¹⁴), via formation of the corresponding carboxy group and thencondensation with the appropriate amine of formula HNR¹³R¹⁴. The carboxygroup is formed by reaction of the intermediate organolithium reagentwith carbon dioxide in a suitable organic solvent such as THF. Thesubsequent condensation reaction with the appropriate amine of formulaHNR¹³R¹⁴ is preferably carried out in the presence of a coupling reagentsuch as carbonyldiimidazole (CDI) in a suitable solvent such as dioxan.

Similarly the halogen can be converted in one step to the correspondingcarboxamido group by reaction of the organolithium reagent describedabove with trimethylsilyl isocyanate.

Alternatively the halogen can be converted to the correspondingcarboxamido group by initial reaction with an inorganic cyanide, such aszinc cyanide, in the presence of a palladium catalyst, such astris(dibenzylideneacetone)dipalladium, and a phosphine ligand, such astri-tert-butylphosphine. The reaction is carried out in a suitablesolvent such as dioxan, usually at reflux. The resultant nitrile is thenhydrolysed to the carboxamide under basic conditions, such as hydrogenperoxide with potassium carbonate. The reaction is carried out in asuitable solvent such as DMSO in methanol. In this conversion there isno necessity to protect the alcohol function.

Then the alcohols are deprotected using standard methods known in theliterature, such as Greene and Wuts, Protecting Groups in OrganicSynthesis, 3rd. Ed., John Wiley & Sons.

Compounds of the formula (VI) wherein

and R⁵ and R⁶ are hydrogen can be prepared from the appropriate ketonesof formula (VII) as shown in Scheme 1 below.

Such ketones react with activated ylides such as for example aphosphonate of the formula (R^(ii)O)₂P(O)CH₂CO₂R^(iii), wherein R^(ii)and R^(iii) are each C₁₋₆ alkyl, in the presence of a base such assodium hydride in a suitable solvent such as for example THF to form thecorresponding unsaturated ester (VIII). The alkene is reduced forexample via hydrogenation in the presence of a catalyst such as Pd oncharcoal in a suitable solvent such as ethanol or methanol.

Unsaturated esters of formula (IX) can be prepared via isomerisation ofthe corresponding unsaturated ester of formula (VIII) as shown in scheme1 above. This reaction is carried out in the presence of a suitable basesuch as sodium methanide in a suitable solvent such as THF.

Compounds of the formula (VI) wherein

can be prepared as shown in scheme 2 from the appropriate lactones offormula (X).

Such lactones are converted to the corresponding hemiacetals viareduction of the lactone using a reducing agent such asdiisobutylaluminium hydride (DIBAL) in the presence of a suitablesolvent such as dichloromethane, followed by the protection of theintermediate hemiacetal with a suitable protecting group such asacetate. The protected hemiacetal is reacted with an appropriateorganozincate derived from the corresponding haloacetal of formulaL^(i)-CH₂—CO₂R wherein L^(i) is a halogen group such as bromo or iodoand R has the value defined above, in the presence of a Lewis acid suchas trimethylsilyltriflate to form esters of the formula (VI)^(ii).

Alternatively the hemiacetal is reacted directly with an activated ylidsuch as for example a phosphonate of the formula(R^(ii)O)₂P(O)CH₂CO₂R^(iii), wherein R^(ii) and R^(iii) are each C₁₋₆alkyl, in the presence of a base such as caesium carbonate in a suitablesolvent such as for example THF, to form the corresponding ester(VI)^(ii). Such esters can be converted to the corresponding alcoholsusing the method mentioned above. Alternatively they can be hydrolysedin acidic conditions to the acid, followed by formation of the mixedanhydride and final reduction of such a mixed anhydride to thecorresponding alcohol of formula (V)^(ii).

Alternatively compounds above wherein n is 2 can be synthesised viastandard acid catalysed cyclisation of the corresponding phenyl alcoholof formula (XII) with an appropriate aldehyde of the formulaCHO—CH₂—COOR^(iv) or its corresponding acetal of the formula(R^(v)O)₂CH—CH₂—COOR^(ir), wherein R^(iv) and R^(v) are eachindependently a C₁-C₆ alkyl group, in the presence of a Lewis acid suchas titanium tetrachloride in a suitable solvent such as dichloromethane,see Scheme 3 below.

Compounds of the formula (V) wherein

can be prepared as shown in scheme 4 from the appropriate quinolines offormula (XIII).

Such quinolines are converted to the corresponding 1,2,3,4tetrahydroquinolines by reduction, for example by hydrogenation in thepresence of ammonium formate and a suitable catalyst such as Palladiumon charcoal in a suitable solvent such as methanol. Thetetrahydroquinoline is then alkylated with allyl halide for exampleallyl bromide in the presence of a suitable base such as sodium hydridein a suitable solvent such as dimethylformamide (DMF). The double bondof the allyl group is then cleaved for example via ozonolysis. Theintermediate ozonide formed is reduced with a suitable reducing agentsuch as sodium borohydride to give the corresponding alcohol.Alternatively such a double bond can be cleaved for example with osmiumtetroxide and sodium periodate in the presence of a suitable reducingagent such as sodium borohydride.

Compounds of the formula (V) wherein

can be prepared as shown in scheme 5 from the appropriate2-oxo-1,2,3,4-tetrahydroquinoline of formula (XVI).

Such 2-oxo-1,2,3,4-tetrahydroquinolines can be alkylated with an allylhalide for example allyl bromide in the presence of a suitable base suchas sodium hydride in a suitable solvent such as dimethylformamide (DMF).The allyl group can be converted to the corresponding alcohol using themethod shown above.

Compounds of the invention can also be synthesised via reaction of thecorresponding amine of the formula (XIX) with a compound of the formulaZ-L^(iii) wherein L^(iii) is a leaving group such as triflate or ahalide such as bromide or iodide.

Such reactions are usually carried out in the presence of a palladiumcatalyst such as palladium acetate and a base such as potassiumtertbutoxide.

Some intermediates of the general formula Z-L^(iii) wherein L^(iii) is ahalogen group such as bromo are commercially available. Alternatively,they can be synthesised from known literature routes, such as bybrominating the corresponding aromatic group with NBS. Intermediateswherein L^(iii) is a triflate can be prepared using methods known in theart such as from the corresponding ketones in the presence of triflicanhydride. Such intermediates are illustrated in scheme 7 for compoundwherein Z is (i) and (xii), but it will be appreciated that such methodcan be used for any values of Z. It will also be appreciated that forcompounds wherein Z is (xxi) to (xxv) the linker -T- might have to beprotected during any of these processes, especially for compoundswherein -T- is —C(O)— or —CH═CH—.

Compounds of formula (I) wherein R¹ is

can be synthesised from the corresponding amide intermediates of formula(V)^(v) wherein the alcohol moiety is protected with an appropriatealcohol protecting group P, such as those shown in Greene and Wuts,Protecting Groups in Organic Synthesis, 3rd. Ed., John Wiley & Sons.

Such intermediates are cyclised via reaction with dimethylformamidedimethylacetal in a suitable solvent such as toluene, followed byreaction with the corresponding hydrazine of the formula R¹³—NH—NH₂ in asuitable solvent such as for example methanol. Then the alcohols aredeprotected using methods known in the art such as those shown in Greeneand Wuts, Protecting Groups in Organic Synthesis, 3rd. Ed., John Wiley &Sons.

As described above the compounds of the invention can have an asymmetriccentre, said compounds, for example compounds of formula Ia, can beprepared in a similar way as those compounds of general formula I, byreacting a compound of formula:

where n and R¹ to R⁸ have the values defined for formula I above, —W— is—CH₂—, —O—, or —S—, and L^(iv) is a leaving group, with a compound offormula (IV).

The reaction is preferably carried out using the same conditions asdescribed above, such as in the presence of a base such as potassiumcarbonate, in an organic solvent such as a polar aprotic solvent, forexample, acetonitrile, at a temperature of from 20° C. to 100° C.Examples of suitable leaving groups are mesylate, tosylate, triflate,chloride, bromide and iodide.

Intermediate compounds of formula (IIIa) can, for example, be preparedfrom the corresponding alcohols of the formula:

where the substituents have the values defined for formula (IIIa) above,using standard methods known in the literature such as the ones shown inMarch, Advanced Organic Chemistry, Fourth Edition, for example themethods mentioned on pages 353 and 354.

Said alcohols of formula (Va) can be prepared via methods known in theliterature such as for example the procedure described in TenBrink etal., J. Med. Chem., 1996, 39, 2435-2437.

In the same way compounds of the invention having two asymmetric carbonatoms such as compounds of formula (Ib), can be prepared by reacting thecorresponding chiral intermediates such as a compound of formula (IIIa)with a compound of the formula:

For compounds of formula (Ic), by reacting a compound of formula (IIIa)with a compound of the formula:

where the substituents have the values defined for formulae (Ib) and(Ic) above.

The reaction is preferably carried out in the presence of a base such aspotassium carbonate, in an organic solvent such as a polar aproticsolvent, for example, acetonitrile, at a temperature of from 20° C. to100° C. Examples of suitable leaving groups are mesylate, tosylate,triflate, chloride, bromide and iodide.

It will be appreciated that compounds of formulae (Ib) and (Ic) can alsobe produced by the preparation of compounds of formula (Ia) as theracemic mixture, followed by the separation of the correspondingisomers.

Intermediates of formula (IVa) wherein —X—Y— is —N(Z)-CH₂— can besynthesised via reaction of the unprotected piperazine of the formula

with a compound of formula Z-L^(iii).

Such reactions are usually carried out in the presence of a palladiumcatalyst such as palladium acetate, BINAP((R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and a base such asCaesium carbonate.

In the same way intermediates of formula (IVb) wherein —X—Y— is—N(Z)-CH₂— can be synthesised via reaction of the unprotected piperazineof the formula

with a compound of formula Z-L^(iii), using the same reaction conditionsas described above.

Methods for the preparation of intermediates of formula (IVa) arefurther illustrated below. Said methods refer to compounds wherein —X—Y—is —N(Z)-CH₂— for methods (a) to (1) or —C(Q)(Z)-CH₂— for method (m),and wherein Z has different values and several substitution patterns.Additionally methods (n) to (s) illustrate methods for the preparationof intermediates of formula (IIIa) with different values of R¹. Any ofvariety of intermediates of formula (IVa) can be used for thepreparation of the starting materials and can equally be used to obtainthe corresponding intermediates of formula (IVb). They all use thecommon step of reaction of the unprotected piperazine with a compound offormula Z-L^(iii) using the conditions described above, unless statedotherwise.

Method a)

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁶ is CN canbe prepared as shown in the scheme below:

via conversion of the naphthoic acid into the correspondingnaphthonitrile, followed by reaction with the unprotected piperazine asdescribed above. The last reaction is preferably carried out in asolvent such as toluene and in the presence of a Palladium catalyst suchas tris(dibenzylideneacetone)dipalladium(0),(R)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl (BINAP), and a base suchas sodium tert-butoxide.

The acid moiety is converted to the nitrile using general methods knownin the art, for example the reaction can be carried out in the presenceof an activating reagent such as methanesulfonyl chloride and reactingthe reactive intermediate with ammonia in an organic solvent such aspyridine. Further addition of methanesulfonyl chloride dehydrates theintermediate carboxamide to the nitrile.

Method b)

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁹ is Cl canbe prepared as shown in the scheme below:

via conversion of the alcohol into a suitable leaving group L^(iii),followed by reaction with the unprotected piperazine, as describedabove. When the L^(iii) group is a triflate, reaction of the alcoholcan, for example, be carried out in an organic solvent such as THF, inthe presence of a base such as sodium tert-butoxide and a triflatingagent such as, for example, N-phenyltrifluoromethanesulfonimide.Method c)

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁹ is CN canalso be prepared as shown in the scheme below:

via conversion of the amino group of the correspondingaminonaphthonitrile into a suitable leaving group L^(iii), followed byreaction with the unprotected piperazine, as described above. When theL^(iii) group is a halide, the reaction can, for example, be carried outin the presence of copper(I)halide and nitrous acid, formed from amixture of aqueous sodium nitrite and an acid such as hydrochloric acid.Method d)

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁶ and R¹⁹are both F can be prepared as shown in the scheme below:

An iodo group is introduced into the napthalene ring, followed byprotection of the nitrogen atom with a suitable protecting group P,conversion of the iodo group to a fluoro group and final deprotection.

The introduction of the iodo group is preferably carried out usinggeneral iodination conditions, such as in the presence of a mixture ofbis(pyridine)iodonium(I) tetrafluoroborate and tetrafluoroboric acid, inan organic solvent such as dichloromethane.

The nitrogen atom can be protected using general conditions as describedin Greene and Wuts, Protecting Groups in Organic Synthesis, 3rd. Ed.,John Wiley & Sons. A suitable protecting group is for example CBZ. Saidprotecting groups can be cleaved following the procedures also describedin Greene and Wuts, Protecting Groups in Organic Synthesis, 3rd. Ed.,John Wiley & Sons.

The iodo group is converted to a fluoro group in the presence ofN-fluorobenzenesulfonimide and a base such as tert-butillithium, in anorganic solvent such as tetrahydrofuran.

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁶ is F andR¹⁹ is CN can be prepared as shown in the scheme below:

via conversion of the iodo group into the corresponding nitrile group.

The reaction is preferably carried out in the presence of a cyanide suchas potassium cyanide, a catalyst such as copper(I) iodide and apalladium catalyst such as tetrakis(triphenylphosphine)palladium(0), inan organic solvent such as tetrahydrofuran. The reaction mixture ispreferably heated, for example, at a temperature around 100° C.

Method e)

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁶ and R¹⁹are both methyl can be prepared as shown in the scheme below:

wherein the 1H,3H-naphtho[1,8-cd]pyran-1,3-dione is reduced to thecorresponding 1H,3H-naphtho[1, 8-cd]pyran. Then the pyran ring of the1H,3H-naphtho[1,8-cd]pyran is then opened to give the correspondingbis(bromomethyl)naphthalene derivative, which is subsequently convertedto the dimethyl compound. Reaction with the corresponding unprotectedpiperazine is performed as described above.

The reduction is preferably carried out in the presence of a reducingagent such as sodium borohydride, in an organic solvent such as ethanol,followed by reaction with an acid such as trifluoroacetic acid, in anorganic solvent such as dichloromethane and in the presence of areducing agent such as triethylsilane.

The pyran ring is preferably opened in the presence of a reagent such asboron tribromide, in an organic solvent such as dichloromethane atreflux.

The dimethyl compound is preferably prepared in the presence of areducing agent such as sodium borohydride, in the presence of anactivating agent such as silver nitrate, in an organic solvent such asdimethylformamide.

Method f)

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁶ is F canbe prepared as shown in the scheme below:

wherein the naphthol compound is protected with a suitable alcoholprotecting group P″, as described in Greene and Wuts, Protecting Groupsin Organic Synthesis, 3rd. Ed., John Wiley & Sons, followed byconversion of the bromo group into a fluoro group. The alcohol isdeprotected and converted into a suitable leaving group L^(iii), thenreacted with the corresponding unprotected piperazine, as describedabove.

The alcohol can be protected using general conditions, as described inGreene and Wuts, Protecting Groups in Organic Synthesis, 3rd. Ed., JohnWiley & Sons, a suitable protecting group is, for example,tert-butyldimethylsilane. Said protecting groups can be cleavedfollowing the procedures also described in Greene and Wuts, ProtectingGroups in Organic Synthesis, 3rd. Ed., John Wiley & Sons.

The bromo group is converted to a fluoro group in the presence ofN-fluorobenzenesulfonimide and a base such as tert-butillithium, in anorganic solvent such as tetrahydrofuran.

The conversion of the alcohol into a suitable leaving group such as atriflate can be carried out in an organic solvent such as THF in thepresence of a base such as sodium tert-butoxide and a triflating agentsuch as, for example, N-phenyltrifluoromethanesulfonimide.

Method g)

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁶ is Cl canalso be prepared as shown in the scheme below:

via conversion of the alcohol into a suitable leaving group L^(iii), theamino group into a chloro group, followed by reaction with theunprotected piperazine, as described above. When the L^(iii) group is atriflate, the first reaction can, for example, be carried out in anorganic solvent such as THF, in the presence of a base such as sodiumtert-butoxide and a triflating agent such as, for example,N-phenyltrifluoromethanesulfonimide.

The amino group is preferably reacted with copper(I)chloride and nitrousacid, prepared from a mixture of aqueous sodium nitrite and an acid suchas hydrochloric acid.

Method h)

Intermediates of formula (IVa) wherein Z is (xii)_(a) and R¹⁶ is CN canalso be prepared as shown in the scheme below:

via conversion of the alcohol into a suitable leaving group L^(v),deprotection of the ether to give an alcohol, displacement of L^(v) witha nitrite group, conversion of the alcohol into a suitable leaving groupL^(iii), followed by reaction with the unprotected piperazine, asdescribed above.

The conversions of the alcohol into suitable leaving groups L^(iii) andL^(v), when the L^(iii) and L^(v) groups are triflates can, for example,be carried out in an organic solvent such as THF, in the presence of abase such as sodium tert-butoxide and a triflating agent such as, forexample, N-phenyltrifluoromethanesulfonimide.

The methyl ether is deprotected with boron tribromide in a suitableorganic solvent such as dichloromethane.

The displacement of L^(v) with a nitrile group is preferably carried outby heating the compound in a suitable organic solvent such as DMF, inthe presence of a cyanide such as, for example, zinc cyanide and apalladium catalyst such as tetrakis triphenylphosphine palladium(0).

Method i)

Intermediates of formula (IVa) wherein Z is (xxi), m and s are both 1and -T- is —O—, can be prepared as shown in the scheme below:

wherein the 1H,3H-naphtho[1,8-cd]pyran-1,3-dione is reduced to thecorresponding 1H,3H-naphtho[1,8-cd]pyran, followed by reaction with thecorresponding unprotected piperazine, as described above.

The reduction is preferably carried out in the presence of a reducingagent such as sodium borohydride in an organic solvent such as ethanol,followed by reaction with an acid such as trifluoroacetic acid in anorganic solvent such as dichloromethane and in the presence of an ionicreducing agent such as triethylsilane.

Method j)

Intermediates of formula (IVa) wherein Z is (xxi), and -T- is —CH₂—, canbe prepared as illustrated in the scheme below for compounds wherein mis 1, s is 0 and L^(iii) is a suitable leaving group, such as bromide:

via reaction of the corresponding 5-bromo-1,2-dihydroacenaphthylene withthe corresponding unprotected piperazine as described above.Method k)

Intermediates of formula (IVa) wherein Z is (xxi), both m and s are 0,and -T- is —CH═CH— can be prepared from the corresponding1,2-dihydroacenaphthylene as shown in the scheme below:

via aromatisation in the presence of a suitable reagent such as DDQ, andin a suitable solvent such as dichloromethane, followed by reaction withthe corresponding unprotected piperazine, as described above.Method l)

Intermediates of formula (IVa) wherein Z is (xxi), m and s are both 1and -T- is —S—, can be prepared as shown in the scheme below:

wherein the bis(bromomethyl)naphthalene intermediate (described above)is cyclised to give the thiopyran ring, followed by reaction with thecorresponding unprotected piperazine, as described above.

The cyclisation is preferably carried out with a sulfide such sodiumsulfide nonahydrate, in an organic solvent such as dimethylformamide.

Compounds of formula I wherein Z is (xxi), m is 0, s is 1, and -T- is—C(O)— can be prepared from the corresponding 1,2-dihydroacenaphth-1-ol,as shown in the scheme below:

Method m)

Intermediates of formula (IVa) wherein —X—Y— is

Q is hydrogen and for example Z is (xii)_(a) can be prepared as shown inthe scheme below:

via reaction of the Z-L^(vi) compound, wherein L^(vi) is a suitableleaving group such as triflate, with a N-protected4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridine,(which can be synthesised according to the procedure described by PaulR. Eastwood in Tetrahedron Letters, 2000, 41, 3705-3708). The reactionis carried out in the presence of a base such as potassium carbonate anda palladium catalyst such asbis(diphenylphosphino)-ferrocenedichloropalladium(II) in a suitablesolvent such as DMF, to give the corresponding protected3,6-dihydro-1(2H)-pyridine, which is reduced to the correspondingprotected piperidine, and then deprotected.

The piperidine compound can be prepared by reduction with hydrogen inthe presence of a palladium catalyst, such as palladium on carbon in asuitable solvent such as methanol.

The deprotection of the piperidine can be carried out according to thenitrogen-protecting group (P) used. Suitable protecting groups aredescribed in Greene and Wuts, Protecting Groups in Organic Synthesis,3rd. Ed., John Wiley & Sons and include tert-butylcarboxynyl (BOC),which can be deprotected, for example, in a suitable solvent such asdichloromethane and in the presence of trifluoroacetic acid.

Method n)

Intermediates of formula (IIIa) wherein R¹ is

can be prepared from the corresponding protected alcohols of formula(Va) via deprotection following suitable conditions described in Greeneand Wuts, Protecting Groups in Organic Synthesis, 3rd. Ed., John Wiley &Sons. Suitable protecting groups (P′) are also described in the abovereference and include the tertbutyldimethylsilyl group. Said alcohols offormula (Va) can be prepared as shown in the scheme below:

wherein L^(vii) is a suitable leaving group such as bromide, viareaction with the corresponding dioxaborinanyl pyridine. This reactionis preferably carried out in the presence of a suitable solvent such astoluene and in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium and a suitable base such aspotassium hydroxide.Method o)

Intermediates of formula (IIIa) wherein R¹ is SO₂NR¹³R¹⁴ can be preparedfrom the corresponding protected alcohols of formula (Va)^(ii) viadeprotection following suitable conditions described in Greene and Wuts,Protecting Groups in Organic Synthesis, 3rd. Ed., John Wiley & Sons.Suitable protecting groups (P′) are also described in the abovereference and include tertbutyldimethylsilyl groups. Said alcohols offormula (Va)^(ii) can be prepared as shown in the scheme below:

wherein L^(vii) is a suitable leaving group such as bromide, viaformation of the corresponding sulfonamide. This reaction is preferablycarried out in a suitable solvent such as tetrahydrofuran and in thepresence of sulphur dioxide and a suitable base such as n-butyllithium,followed by reaction in a suitable solvent such as dichloromethane inthe presence of N-chlorosuccinimide and the corresponding amine(HNR¹³R¹⁴).Method p)

Intermediates of formula (IlIa) wherein R¹ is —(CH₂)_(t)—R²¹′, t is 0and R²¹′ is a protected amino group can be prepared from thecorresponding protected alcohols of formula (Vb), as shown in schemebelow:

wherein L^(vii) is a suitable leaving group such as bromide, viareaction with a suitable imine, such as for example benzophenone imine.Suitable protecting groups (P′) are described in Greene and Wuts,Protecting Groups in Organic Synthesis, 3rd. Ed., John Wiley & Sons, andinclude tertbutyldimethylsilyl groups. Said protected alcohols aredeprotected following suitable conditions as also described in the abovereference, and are subsequently converted to intermediates of formula(IIIa)^(i).

Said intermediates of formula (IIIa)^(i) are reacted with thecorresponding unprotected piperazine using standard conditions describedabove. The last step is the deprotection of the protected amino group togive the corresponding free amino compound of formula (I_(f)).

The displacement of the L^(vii) group is preferably carried out in asuitable solvent such as toluene, in the presence of a catalyst such astris(dibenzylidene-acetone)dipalladium, a suitable ligand such as BINAPand a suitable base such as sodium tert-butoxide.

The amino group is preferably deprotected in basic mild conditions suchas in the presence of hydroxylamine hydrochloride and sodium acetate, ina suitable solvent such as methanol.

Compounds of formula (I_(f)) can be used as intermediates for thesynthesis of compounds of formula I wherein R¹ is —(CH₂)_(t)—R²¹,wherein t is 0 and R²¹ is

via reaction with L^(viii)-CH₂—(CH₂)_(v)—CH₂—O—CO-L^(ix) wherein bothL^(viii) and L^(ix) are suitable leaving groups such as for examplechloride, in the presence of a suitable base such as pyridine, in asuitable solvent such as DMF, as shown in the scheme below:

Method q)

Intermediates of formula (IIIa) wherein R¹ is —CH₂—R²¹ can be preparedfrom the corresponding protected alcohols of formula (Vb), as shown inscheme below:

wherein L^(vii) and L^(x) are suitable leaving groups, and P′ is asuitable alcohol protecting group such as described in Greene and Wuts,Protecting Groups in Organic Synthesis, 3rd. Ed., John Wiley & Sons, forexample a tertbutyldimethylsilyl group.

Intermediate (Vb) is converted to the corresponding carboxaldehyde viareaction with dimethylformamide in the presence of a suitable base suchas tert-butyllithium and in a suitable solvent such as THF. Saidaldehyde is reduced to the corresponding alcohol using standard reducingagents, such as for example sodium borohydride in a suitable solventsuch as ethanol. The resulting primary alcohol is converted into asuitable leaving group L^(x), such as for example mesylate, in thepresence of mesyl chloride and a suitable base such as triethylamine.Said mesylate is subsequently displaced with the corresponding nitrogencontaining compound HR²¹ in the presence of a suitable base, such as forexample sodium hydride, and in a suitable solvent such as DMF.

Method r)

Intermediates of formula (IIIa) wherein R¹ is —(CH₂)_(t)—R²¹, t is 0 andR²¹ is

can be prepared from the corresponding protected alcohols of formula(Vb), as shown in scheme below:

wherein L^(vii) is a suitable leaving group, such as for examplebromide, chloride, iodide or mesylate. P′ is a suitable alcoholprotecting group such as described in Greene and Wuts, Protecting Groupsin Organic Synthesis, 3rd. Ed., John Wiley & Sons, for example atertbutyldimethylsilyl group.

L^(vii) of intermediate (Vb) is displaced via reaction with thecorresponding triazole, in a suitable solvent such as DMF and in thepresence of a catalytic amount of copper iodide and a suitable base suchas potassium carbonate.

It will be appreciated that the above reaction scheme is illustrated forcompounds wherein the alcohol is protected but it can equally be carriedout for the corresponding unprotected alcohols wherein P′ is hydrogen.

Method s)

Intermediates of formula (IIIa) wherein R¹ is —(CH₂)_(t)—R²¹, t is 0 andR²¹ is

can be prepared from the corresponding protected alcohols of formula(Vb), as illustrated in the scheme below, for compounds wherein R²¹ is2-imidazolidinone:

wherein L^(vii) is a suitable leaving group such as for example bromide,chloride, iodide or mesylate. P′ is a suitable alcohol protecting groupsuch as described in Greene and Wuts, Protecting Groups in OrganicSynthesis, 3rd. Ed., John Wiley & Sons, for example atertbutyldimethylsilyl group.

L^(vii) of intermediate (Vb) is displaced via reaction with thecorresponding imidazolidinone, in a suitable solvent such as DMF and inthe presence of a catalytic amount of copper iodide and a suitable basesuch as potassium carbonate.

It will be appreciated above reaction scheme is illustrated forcompounds wherein the alcohol is protected but it can equally be carriedout for the corresponding unprotected alcohols wherein P′ is hydrogen.

Alternatively, compounds of formula I wherein R¹ is —(CH₂)_(t)—R²¹ and tis 0, can be prepared from the reaction of compounds of formula(IIIa)^(ii) as shown in scheme below:

wherein L^(xi) and L^(xii) are suitable leaving groups. Intermediate(IIIa)^(ii) is reacted with a compound of formula (IVa), followingstandard procedures described above, to give a compound of formula (Ig).L^(xi) of intermediate (Ig) is converted to R²¹ via reaction with HR²¹,in the presence of a suitable catalyst such astris(dibenzylideneacetone)dipalladium, a suitable ligand such as BINAP,a suitable base such as Caesium Carbonate and in a suitable solvent suchas toluene.

In the same way compounds of formula I wherein R¹ is —(CH₂)_(t)—R²¹ andt is 1, can be prepared from the corresponding nitrites as shown inscheme below:

wherein L^(xiii) is a suitable leaving group such as for examplebromide, chloride, iodide or mesylate. Said leaving group is convertedto the nitrile using standard methods described above. The free alcoholcan be converted to a suitable leaving group which can be displaced witha compound of formula (IVa). Alternatively said alcohol can be oxidisedto the corresponding aldehyde using standard oxidating procedures knownin the literature, followed by reductive amination in the presence ofthe unprotected piperazine using the standard conditions describedabove. The nitrile is then reduced to the corresponding amine in thepresence of a suitable reducing agent such as for example lithiumaluminium hydride. Said amine can be converted to several of the R²¹substituents, such as for example,

via cyclisation in the presence ofL^(viii)-CH₂—(CH₂)_(v)—CH₂—O—CO-L^(ix) as illustrated in method (p)above.

As shown above substituents in any of the aromatic rings, such as R¹ andR², may be present in the starting materials or introduced at anappropriate point in the manufacture of the product compound. Ifnecessary said substituents may be protected during the reactionprocedure.

Compounds of the invention have been demonstrated to be active at theserotonin, 5-HT 1D receptor. Their binding activity has beendemonstrated in a test described by Pullar I. A. et al, European Journalof Pharmacology, 407 (2000), 39-40.

As mentioned above, the compounds of the invention and theirpharmaceutically acceptable salts have useful central nervous systemactivity. They have been shown to increase release of tritiated-5HT fromguinea pig cortical slices in a test with the following procedure.

Cortical slices from the brains of male guinea pigs were incubated with50 nM [³H]-5-HT for 30 minutes at 37° C. The slices were washed in basalbuffer containing 1 μM paroxetine and then transferred to baskets. Thebaskets were used to transfer the tissue between the washing and releasebuffers, all of which contained 1 μM paroxetine.

In order to obtain a stable baseline release, the slices were incubatedfor 11 minutes in buffer and then transferred for 4 minutes to a secondtube containing buffer. Following incubation they were againtransferred, for a further 4 minutes, to a buffer in which NaCl had beensubstituted, on an equimolar basis, to give a KCl concentration of 30 mM(release sample).

The tritium in the tissue samples and in the buffers from the threeincubation periods was estimated by liquid scintillation spectroscopy.Test compound was present throughout the three incubation periods. Thecompounds of the invention enhanced release of 5-HT.

The compounds of the invention are serotonin reuptake inhibitors, andpossess excellent activity as, for example, in the test described byCarroll et al., J. Med. Chem. (1993), 36, 2886-2890, in which theintrinsic activity of the compound to competitively inhibit the bindingof selective serotonin reuptake inhibitors to the serotonin transporteris measured. These results were also confirmed by in vivo tests in whichthe effect of the compound on a behavioural syndrome in mice dosed with5-HTP and a monoamine oxidase inhibitor (MAOI) such as pargyline, ismeasured, see Christensen, A. V., et al., Eur. J. Pharmacol. 41, 153-162(1977).

In view of the selective affinity of the compounds of the invention forthe serotonin receptors, they are indicated for use in treating avariety of conditions associated with serotonin dysfunction in mammalsincluding disorders of the central nervous system such as depression,bipolar disorder, anxiety, obesity, eating disorders such as anorexiaand bulimia, alcoholism, pain, hypertension, ageing, memory loss, sexualdysfunction, psychotic disorders, schizophrenia, gastrointestinaldisorders, headache, cardiovascular disorders, smoking cessation,epilepsy, drug abuse and addiction, emesis, Alzheimer's disease andsleep disorders. The compounds of the invention are principally intendedfor the treatment of depression or anxiety, or disorders with depressiveor anxiety symptoms.

Accordingly the present invention includes the use of a compound offormula I or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of a disorder associatedwith serotonin dysfunction in mammals, including any of the disordersmentioned above.

The compounds of the invention are effective over a wide dosage range,the actual dose administered being dependent on such factors as theparticular compound being used, the condition being treated and the typeand size of animal being treated. However, the dosage required willnormally fall within the range of 0.001 to 20, such as 0.01 to 20 mg/kgper day, for example in the treatment of adult humans, dosages of from0.5 to 100 or 200 mg per day may be used.

The compounds of the invention will normally be administered orally orby injection and, for this purpose, the compounds will usually beutilised in the form of a pharmaceutical composition. Such compositionsare prepared in a manner well known in the pharmaceutical art andcomprise at least one active compound.

Accordingly the invention includes a pharmaceutical compositioncomprising as active ingredient a compound of formula (I) or apharmaceutically acceptable salt thereof, associated with apharmaceutically acceptable diluent or carrier. In making thecompositions of the invention, the active ingredient will usually bemixed with a carrier, or diluted by a carrier, or enclosed within acarrier which may be in the form of a capsule, sachet, paper or othercontainer. More than one active ingredient or excipient may, of course,be employed. The excipient may be a solid, semi-solid or liquid materialwhich acts as a vehicle, excipient or medium for the active ingredient.Some examples of suitable excipients are lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, syrup, methyl cellulose, methyl- andpropyl-hydroxybenzoate, talc, magnesium stearate or oil. Thecompositions of the invention may, if desired, be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient.

Depending on the route of administration, the foregoing compositions maybe formulated as tablets, capsules or suspensions for oral use andinjection solutions or suspensions for parenteral use or assuppositories. Preferably the compositions are formulated in a dosageunit form, each dosage containing from 0.5 to 100 mg, more usually 1 to100 mg, of the active ingredient.

The following Preparations and Examples illustrate routes to thesynthesis of the compounds of the invention.

PREPARATION(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide MethodA

a) 2-(6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid ethyl ester

A solution of 3-bromophenethyl alcohol (15 g, 74.6 mmol) andethyl-3-3-diethoxypropionate (17.1 g, 89.9 mmol) in dichloromethane (60mL) under an atmosphere of nitrogen was cooled to −10° C. and treatedwith a 4N solution of titanium tetrachloride in dichloromethane (61.5ml, 3.3 equiv.) over a period of 15 minutes. The reaction mixture wasthen allowed to warm to room temperature. Analysis of an aliquot by HPLCindicated that the reaction was complete after 3 h at ambienttemperature. The reaction mixture was then cooled to 0° C. and waterslowly added (over 15 minutes) maintaining the temperature between 0 and10° C. The mixture was agitated for an additional period of 15 minutesand layers were separated. After washing with water (60 mL), 0.5N NaOH(80 mL), then brine (80 mL), the organic layer was concentrated in vacuoto give the title compound as an oil.

b) 2-(6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid

2-(6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid ethyl ester (20g, 66.9 mmol) was dissolved in absolute ethanol (40 mL). The mixture wascooled to 0° C. and 4N NaOH (22 mL) was added over five minutes. Thereaction mixture was then stirred for 1.5 h at room temperature. Water(22 mL) was added, and the solution washed with dichloromethane (70 mL).The aqueous layer was collected and acidified with 6N HCl (17 mL) andextracted with dichloromethane (70 mL). The organic layer wasconcentrated in vacuo to give an off-white solid. This solid wassuspended in toluene (66 mL) and heated to 100° C. The resultingsolution was cooled to 80° C. and cyclohexane (66 mL) added. Theresulting suspension was cooled to room temperature and stirred for anhour. The solid was then filtered off, washed with cyclohexane (20 mL),and dried at 40° C. in vacuo to give the title compound as a whitesolid.

c) 2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid

To a suspension of 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)aceticacid (55 g, 203 mmol) in acetonitrile (375 mL) and water (40 mL) wasadded a solution of (R)-1-(4-methylphenyl)ethylamine (27.45 g, 203 mmol)in acetonitrile (370 mL). The mixture was heated to reflux and theresulting solution cooled to room temperature. A precipitate appearedupon cooling. After stirring for 2 h the salt was filtered off, washedwith 95/5 acetonitrile/water (80 mL), and dried in vacuo. The salt wasrecrystallized in 95/5 acetonitrile/water to give a solid which wassuspended in water (390 mL) and treated with 6N HCl (17 mL). Afterstirring for 1.5 h, filtration, washing, and drying gave the titlecompound (98% e.e.) as a white solid.

d) 2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol

To a solution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)aceticacid (21.3 g, 78.6 mmol) in anhydrous THF (65 mL) under an atmosphere ofnitrogen and cooled to 0° C., was added dropwise borane.THF complex inTHF (1M) (94 mL, 94 mmol). After stirring for 1 h between 0 and 10° C.,the reaction mixture was treated with aqueous sodium carbonate thenextracted into toluene. The organic layer was washed with dilute aqueoushydrochloric acid, then concentrated in vacuo to give the title compoundas a white solid.

e) (1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile

A suspension of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol(300 g, 1.17 mol), copper(I) cyanide (209 g, 2.34 mol), and copper(I)iodide (33.3 g, 0.18 mol) in dry DMF (1.16 L), under an atmosphere ofnitrogen, was heated to 140° C. After 8 h at this temperature, HPLCanalysis of an aliquot indicated that the reaction was complete. Thereaction mixture was cooled to room temperature and poured into anaqueous solution of ethylenediamine (3 L, v/v 3/1) then extracted intotoluene. The combined organic layers were washed with water andconcentrated in vacuo to give the crude title compound. This material isused without further purification in the subsequent step.

f) (1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide

To a solution of crude(1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (178g, 0.88 mol) in methanol (460 mL) and DMSO (125 mL) was added potassiumcarbonate (13 g, 94 mmol). 35% hydrogen peroxide (102 mL) was then addeddropwise while maintaining the temperature of the mixture below 50° C.The reaction mixture was then allowed to stir for 1 h at ambienttemperature. Analysis of an aliquot by silica TLC (ethyl acetate)indicated that the reaction was complete. Water (130 mL) was added andmethanol removed in vacuo. Water (800 mL) and 1N HCl (100 mL) were addedand the mixture allowed to stir overnight. The solid was filtered,washed with water, and dried. Recrystallization frommethyl(i-butyl)ketone gave the title compound.

Method B

a) 2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl-ethyltert-butyl(dimethyl)silyl ether

A 1M solution of tert-butyldimethylsilyl chloride in dichloromethane (30mL, 30 mmol) was added dropwise under nitrogen to an ice/water-cooledsolution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol(6.7 g, 24.4 mmol), diisopropylethylamine (6.7 g. 51.8 mmol) anddimethylaminopyridine (0.32 g, 2.5 mmol) in dry dimethylformamide (70mL). After stirring overnight at room temperature, the mixture wasquenched with ice/water and extracted with ether (2×). The combinedorganic extracts were washed with water (5×), dried (MgSO₄) andevaporated in vacuo to give an oil. This was purified by flashchromatography on silica, eluting with ethyl acetate/hexane (0:100 to10:90), to give the title compound as oil.

b)(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxylicacid

A 1.7M solution of tert-butyl lithium in pentane (1.75 mL, 2.97 mmol)was added under nitrogen to a solution of2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyltert-butyl(dimethyl)silyl ether (0.5 g, 1.35 mmol) in tetrahydrofuran(10 mL), maintained at −70° C. After stirring for 30 min, carbon dioxidewas bubbled through the reaction mixture for 30 min. After stirring atroom temperature overnight, saturated ammonium chloride in water wasadded and the product extracted into ethyl acetate. The organic extractswere dried (MgSO₄) and evaporated in vacuo to give an oil (0.57 g). Thiswas purified by flash chromatography on silica, eluting with ethylacetate/hexane (0:100 to 25:75) to give the title compound as a whitesolid.

c)(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide

A solution of(1S)-1-(2-{[tert-butyl)dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxylicacid (20.7 g, 61.2 mmol) and 1,1′-cabonyldiimidazole (20 g, 123 mmol) indry tetrahydrofuran (450 mL) was stirred under nitrogen at roomtemperature for 16 h. A 0.5M solution of ammonia in dioxane (620 mL, 310mmol) was added and the mixture stirred at room temperature for 1 day.Water (1 L) was added and the product extracted into dichloromethane(2×1 L). The combined organic extracts were washed with saturatedaqueous sodium bicarbonate (2×500 mL) and brine (2×50 mL), dried (MgSO₄)and evaporated in vacuo to give a solid (21 g). This was purified byflash chromatography on silica, eluting with hexane/ethyl acetate (1:1)then ethyl acetate to give the title compound.

d) (1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide

(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide(1 g, 2.98 mmol) was dissolved in a mixture of acetic acid (10 mL) andwater (5 mL), then stirred for 2 h. The solution was evaporated to givea residue that was dried in vacuo at 55° C. to give the title compoundas a white solid.

2-[(1S)-6-(Aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate

(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide (5 g,22.6 mmol) was dissolved in a mixture of dry tetrahydrofuran (375 mL)and dry dimethylformamide (15 mL) with the aid of gentle heating.Triethylamine (4.6 g, 45.5 mmol) was added, followed by methanesulfonylchloride (2.72 g, 23.8 mmol). The mixture was stirred under nitrogen atroom temperature for 1 day. The reaction mixture was quenched with water(1000 mL) and the product extracted into ethyl acetate (2×500 mL). Thecombined organic extracts were washed with brine (2×500 mL), dried(MgSO₄), and evaporated in vacuo to give the crude product as a whitesolid (6.5 g, 97%). The solid was triturated with ether (300 mL) to give2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate as a white solid.

(3R)-1-(6-Fluoro-1-naphthyl)-3-methylpiperazine

a) 6-Fluoro-3,4-dihydro-1-naphthalenyl trifluoromethanesulfonate

To a stirred solution of 6-fluoro-3,4-dihydro-1(2H)-naphthalenone (0.50g, 3 mmol) in dry THF (25 mL) at −78° C. under nitrogen was addedlithium bis(trimethylsilyl)amide (1M in THF) (3.6 mL, 3.6 mmol) over 5min. The solution was stirred for 1 h, thenN-phenyltrifluoromethanesulfonimide (1.3 g, 3.6 mmol) was added in oneportion and the reaction mixture allowed to warm to room temperature.Stirring was continued for 2 h, then the solvent was removed in vacuo.The residue was dissolved in ethyl acetate and washed with 2M sodiumhydroxide, water, and then brine. The organic extracts were dried(MgSO₄), and concentrated in vacuo. The resultant red oil was purifiedby column chromatography on silica, eluting with ethyl acetate/hexane(1:9), to yield 6-fluoro-3,4-dihydro-1-naphthalenyl trifluoromethanesulfonate as a colourless oil.

b) 6-Fluoro-1-naphthyl trifluoromethanesulfonate

To a solution of 6-fluoro-3,4-dihydro-1-naphthalenyl trifluoromethanesulfonate (0.77 g, 2.8 mmol) in dioxan (15 mL) was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.95 g, 4.2 mmol) and thereaction mixture heated under reflux for 18 h. The solvent was removedin vacuo and the crude product purified by column chromatography onsilica, eluting with hexane, to yield 6-fluoro-1-naphthyltrifluoromethanesulfonate as a white solid.

c) (3R)-1-(6-Fluoro-1-naphthyl)-3-methylpiperazine

To a solution of 6-fluoro-1-naphthyl trifluoromethanesulfonate (0.29 g,1 mmol) in toluene (2 mL) under nitrogen was added (2R)-methylpiperazine(0.10 g, 1.2 mmol), (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (47mg, 0.075 mmol), palladium(II) acetate (11 mg, 0.05 mmol) and caesiumcarbonate (0.46 g, 1.4 mmol). The resulting suspension was heated at110° C. for 16 h. Upon cooling, the mixture was filtered through a shortcelite pad (washing with ethyl acetate), the filtrate concentrated invacuo and the crude product purified by flash column chromatography onsilica gel, eluting with dichloromethane/methanol (7:3), to yield(3R)-1-(6-fluoro-1-naphthyl)-3-methylpiperazine as a brown oil.

(3R)-1-(6-Cyano-1-naphthyl)-3-methylpiperazine

a) 5-Bromo-2-naphthonitrile

To a solution of 5-bromo-2-naphthoic acid (4.3 g, 17 mmol)) in drypyridine (75 mL) at 0° C. was added methanesulfonyl chloride (1.4 mL, 18mmol). After stirring at 0° C. for 1 h, ammonia gas was bubbled throughthe solution for 10 min, whilst maintaining the temperature below 5° C.During the gas addition the solution became viscous, so additional drypyridine (˜30 mL) was added. Excess ammonia was removed in vacuo, thesolution again cooled to 0° C., then treated with additionalmethanesulfonyl chloride (12.5 mL) and allowed to warm to roomtemperature overnight. The solution was poured onto ice cold water, themixture stirred for 30 min and the brown precipitate collected byfiltration, washed on the sinter with ice cold water, then dried invacuo. The crude product was dissolved in hot chloroform (˜35 mL) andinsoluble material filtered off. The chloroform was removed and theresidue dissolved in a minimum volume of ether at reflux. Hexane wasadded until the solution remained turbid at reflux, the solutionfiltered rapidly into a pre-heated flask, and allowed to cool slowly toroom temperature. The precipitate was collected by filtration, washedwith hexane, and dried in vacuo, to yield 5-bromo-2-naphthonitrile.Further crops were obtained by cooling the filtrate at −18° C.overnight.

b) (3R)-1-(6-Cyano-1-naphthyl)-3-methylpiperazine

To a solution of 5-bromo-2-naphthonitrile (0.47 g, 2 mmol) in drytoluene (30 mL) was added tris(dibenzylideneacetone)dipalladium(0) (40mg), (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (82 mg),(2R)-methylpiperazine (0.24 g, 2.4 mmol) and sodium tert-butoxide (0.27g, 2.8 mmol). The solution was evacuated until bubbling started, thenthe atmosphere replaced with nitrogen. This purging and evacuationprocedure was repeated for 15 min, then the mixture heated under refluxfor 8 h. The reaction mixture was cooled to room temperature, dilutedwith ethyl acetate and filtered through celite. The filtrate was washedwith aqueous ammonia, dried (MgSO₄), filtered and evaporated in vacuo.The residue was dissolved in methanol (10 mL) and applied to anactivated SCX cartridge (10 g). The cartridge was washed with methanol(100 mL), then the product isolated by elution with 2M ammonia inmethanol (50 mL). The solvent was removed in vacuo and further purifiedby flash chromatography on silica, eluting with acetone, to yield(3R)-1-(6-cyano-1-naphthyl)-3-methylpiperazine.

(3R)-1-(6-Cyano-1-benzothien-3-yl)-3-methylpiperazine

a) 3-Bromo-1-benzothiophene-6-carbonitrile

To a solution of 1-benzothiophene-6-carbonitrile (2.13 g, 13.4 mmol) indry DMF (20 mL) at −10° C. was added freshly recrystallisedN-bromosuccinimide (2.38 g, 13.4 mmol). The solution was allowed to warmto room temperature and stirred over the weekend. The mixture wasdiluted with water and extracted into diethyl ether, and the organicextract washed with water, then brine. The extracts were dried (MgSO₄),filtered and evaporated in vacuo. The crude product was purified byflash chromatography on silica, eluting with ethyl acetate/hexane (1:9),to yield the title compound as a white solid.

b) (3R)-1-(6-Cyano-1-benzothien-3-yl)-3-methylpiperazine

3-Bromo-1-benzothiophene-6-carbonitrile was coupled with(2R)-methylpiperazine, as described above for(3R)-1-(6-cyano-1-naphthyl)-3-methylpiperazine, to yield(3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine.

EXAMPLE 1(1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

a) (3R)-1-(1,2-Dihydro-5-acenaphthylenyl)-3-methylpiperazine

A mixture of 2-(R)-methylpiperazine (0.124 g, 1.1 mmol),tris(dibenzylideneacetone)dipalladium(0) (49 mg, 0.05 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (69 mg, 0.10 mmol) andsodium tert-butoxide (0.148 g, 1.5 mmol) were stirred in toluene (50 mL)under nitrogen for 15 min to give a blood red solution.5-Bromo-1,2-dihydroacenaphthylene (0.256 g, 1.1 mmol) was added, thesolution stirred under nitrogen and heated at reflux for 3 h. Themixture was cooled, diluted with dichloromethane and filtered throughcelite. The organic phase was washed with water, dried (MgSO₄), filteredand evaporated in vacuo. The crude product was taken forward to the nextstep without further purification.

b)(1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

(3R)-1-(1,2-Dihydro-5-acenaphthylenyl)-3-methylpiperazine (0.138 g, 0.55mmol), 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate (0.15 g, 0.50 mmol), potassium carbonate (0.138 g, 1.0mmol), potassium iodide (0.083 g, 1.0 mmol) and acetonitrile (50 mL)were heated under reflux for 1 day with stirring under nitrogen. Aftercooling to room temperature, the inorganics were filtered off and thesolvent evaporated in vacuo. The crude product was purified bypreparative LC-MS to give the title compound. M+H=456.

The following Examples were prepared by substituting the(2R)-methylpiperazine in the above Example with alternative piperazinesor homopiperazine, as indicated below:

EXAMPLE 2(1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-ethylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

Prepared from 5-bromo-1,2-dihydro-acenaphthylene and(2R)-ethylpiperazine. M+H=470.

EXAMPLE 3(1S)-1-{2-[(2S)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-ethylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

Prepared from 5-bromo-1,2-dihydro-acenaphthylene and(2S)-ethylpiperazine. M+H=470.

EXAMPLE 4(1S)-1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-1H-1,4-diazepin-1-yl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

Prepared from 5-bromo-1,2-dihydro-acenaphthylene and homopiperazine.M+H=456.

EXAMPLE 5(1S)-1-{2-[(2R)-4-(5-Acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

a) 5-Bromoacenaphthylene

To 5-bromo-1,2-dihydroacenaphthalene (0.10 g, 0.43 mmol) indichloromethane (10 mL) was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.117 g, 0.515 mmol) andstirred at room temperature for 1 day. An additional portion of DDQ(0.10 g) was added and the reaction stirred for a further 1 day. Themixture was washed with water and the organic phase dried (MgSO₄),filtered and evaporated in vacuo. The crude product was purified byflash chromatography on silica, eluting with ethyl acetate/heptane (0:10to 1:9), to yield the title compound.

b) (3R)-1-(5-Acenaphthylenyl)-3-methylpiperazine

5-Bromoacenaphthylene was coupled with (2R)-methylpiperazine, asdescribed for Example 1a).

c)(1S)-1-{2-[(2R)-4-(5-Acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

(3R)-1-(5-Acenaphthylenyl)-3-methylpiperazine was condensed with2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate, as described for Example 1b), to yield the titlecompound. M+H=454.

EXAMPLE 6(1S)-1-{2-[(2R)-4-(1-Oxo-1,2-dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

a) 5-Bromo-1,2-dihydro-1-acenaphthylenol

To 1,2-dihydro-1-acenaphthylenol (0.34 g, 2 mmol) in dry DMF (10 mL) wasadded recrystallised N-bromosuccinimide (0.39 g, 2.2 mmol), and themixture stirred for 3 h under nitrogen. The solution was poured ontowater (500 mL) and the precipitate filtered off. The resultant solid wasredissolved in methanol, filtered and evaporated in vacuo to yield thetitle compound as a brown solid.

b)[(5-Bromo-1,2-dihydro-1-acenaphthylenyl)oxy](tert-butyl)diphenylsilane

To 5-bromo-1,2-dihydro-1-acenaphthylenol (0.25 g, 1 mmol) in dry THF (30mL) was added chloro(tert-butyl)diphenylsilane (0.275 g, 1 mmol) andimidazole (0.34 g, 5 mmol), and the reaction stirred at room temperatureunder nitrogen for 18 h. The mixture was diluted with diethyl ether,filtered through a pad of silica, and evaporated in vacuo. Purificationby flash chromatography on silica, eluting with ethyl acetate/hexane(1:9 to 1:1), yielded the title compound as a colourless oil.

c)(3R)-1-(1-{[tert-Butyl(diphenyl)silyl]oxy}-1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine

[(5-Bromo-1,2-dihydro-1-acenaphthylenyl)oxy](tert-butyl)diphenylsilanewas coupled with (2R)-methylpiperazine, as described for Example 1a).

d)(1S)-1-{2-[(2R)-4-(1-{[tert-Butyl(diphenyl)silyl]-oxy}-1,2-dihydro-5-acenaphthylenyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

(3R)-1-(1-{[tert-Butyl(diphenyl)silyl]oxy}-1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazinewas condensed with2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate, as described for Example 1b).

e)(1S)-1-{2-[(2R)-4-(1-Hydroxy-1,2-dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

To a solution of(1S)-1-{2-[(2R)-4-(1-{[tert-butyl(diphenyl)silyl]oxy}-1,2-dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide(1.72 g, 2.43 mmol) in dry THF (70 mL) was slowly addedtetrabutylammonium fluoride (1M solution in THF) (2.9 mL, 2.92 mmol),and the mixture stirred for 18 h at room temperature. Dichloromethanewas added to the reaction, which was then washed with water. Thecombined organic phases were dried (MgSO₄), filtered and evaporated invacuo to yield a brown oil. The residue was dissolved in methanol andapplied to an activated SCX-2 ion exchange cartridge. The cartridge waswashed with methanol, then the product isolated by elution with 2Mammonia in methanol. The solvent was removed in vacuo and the crudeproduct further purified by preparative LC-MS, to yield the titlecompound.

f)(1S)-1-{2-[(2R)-2-Methyl-4-(1-oxo-1,2-dihydro-5-acenaphthylenyl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

To a solution of(1S)-1-{2-[(2R)-4-(1-hydroxy-1,2-dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide(0.10 g, 0.21 mmol) in dry DMF (2 mL), cooled to 0° C. under nitrogen,was added pyridinium dichromate (0.08 g, 0.21 mmol), and the mixturestirred for 4 h, allowing the reaction to warm to room temperature. Afurther equivalent of pyridinium dichromate was added and the reactionstirred for a further 1 h. The mixture was poured onto water and theresultant precipitate filtered off. Purification by preparative LC-MSyielded(1S)-1-{2-[(2R)-2-methyl-4-(1-oxo-1,2-dihydro-5-acenaphthylenyl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide.M+H=470.

EXAMPLE 7(1S)-1-{2-[(2R)-2-Methyl-4-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

a) 6-Bromo-1H,3H-naphtho[1,8-cd]pyran

To 6-bromo-1H,3H-naphtho[1,8-cd]pyran-1,3-dione (1.5 g, 5.4 mmol) inethanol (10 mL) was added sodium borohydride (0.41 g, 10.8 mmol) and themixture stirred at room temperature for 1 h. The reaction was quenchedwith 3M hydrochloric acid and extracted into dichloromethane. Thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuo.The residue was dissolved in dichloromethane and trifluoroacetic acid(1.05 mL, 13.53 mmol) and triethylsilane (4.3 mL, 27 mmol) added. Afterstirring for 5 min at room temperature, the solvent was removed in vacuoand the residue purified by column chromatography on silica gel, elutingwith dichloromethane, to yield 6-bromo-1H,3H-naphtho[1,8-cd]pyran as awhite solid.

b) (3R)-3-Methyl-1-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazine

A mixture of 6-bromo-1H,3H-naphtho[1,8-cd]pyran (0.30 g, 1.2 mmol),2-(R)-methylpiperazine (0.145 g, 1.44 mmol),tris(dibenzylideneacetone)dipalladium(0) (55 mg, 0.06 mmol),rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (56 mg, 0.09 mmol) andsodium tert-butoxide (0.162 g, 1.68 mmol) in toluene (5 mL) was heatedunder reflux for 2 h. The solvent was evaporated in vacuo and the crudemixture purified by column chromatography on silica gel, eluting withdichloromethane/methanol (9:1), to yield(3R)-3-methyl-1-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazine as an orangesolid.

c)(1S)-1-{2-[(2R)-2-Methyl-4-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

(3R)-3-Methyl-1-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazine was coupledwith 2-[(1S)-6-aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate as described for Example 1b), to yield(1S)-1-{2-[(2R)-2-methyl-4-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide.M+H=472.

EXAMPLE 8(1S)-1-{2-[(2R)-2-Methyl-4-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

a) 6-Bromo-1H,3H-naphtho[1,8-cd]thiopyran

A mixture of 1-bromo-4,5-bis(bromomethyl)-naphthalene (0.38 g, 0.97mmol) and sodium sulfide nonahydrate (0.25 g, 1.04 mmol) indimethylformamide (13 mL) was stirred at room temperature for 5 h, inthe presence of sodium sulfate as scavenger for the water. The reactionmixture was poured into water and extracted into diethyl ether. Thecombined organic extracts were washed with water, dried (Na₂SO₄) andconcentrated to dryness, to yield 6-bromo-1H,3H-naphtho[1,8-cd]thiopyranas a pale yellow solid.

b) (3R)-3-Methyl-1-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazine

The procedure used for the synthesis of(3R)-3-methyl-1-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazine (Example5b)) was followed, using 6-bromo-1H,3H-naphtho[1,8-cd]thiopyran asstarting material and making non-critical variations, to obtain thetitle compound(3R)-3-methyl-1-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazine as brownsolid.

c)(1S)-1-{2-[(2R)-2-Methyl-4-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

(3R)-3-Methyl-1-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazine wascoupled with2-[(1S)-6-aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate as described for Example 1b), to yield(1S)-1-{2-[(2R)-2-methyl-4-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide.M+H=488.

EXAMPLE 9(1S)-1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)-1-piperidinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

a) tert-Butyl4-(1,2-dihydro-5-acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate

To a solution of 5-bromoacenaphthylene (1.00 g, 4.29 mmol) in dry THF(20 mL), under nitrogen at −78° C., was added a solution ofn-butyllithium (2.5M in hexanes) (1.89 mL, 4.72 mmol) over a period of30 min. The resulting deep red solution was left to stir for a further30 minutes at −78° C. A solution of tert-butyl4-oxo-1-piperidinecarboxylate (0.94 g, 4.72 mmol) in dry THF (10 mL) wasthen added over 30 min. After 2.5 h a cooled solution of saturatedammonium chloride (30 mL) was added, the reaction mixture allowed towarm to room temperature and then extracted with diethyl ether. Thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuoto yield a thick, yellowish tan oil. This oil was purified by flashchromatography on silica, eluting with a methanol/dichloromethanegradient, to yield tert-butyl4-(1,2-dihydro-5-acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate as asticky yellow residue.

b) 4-(1,2-Dihydro-5-acenaphthylenyl)piperidine

To a solution of tert-butyl4-(1,2-dihydro-5-acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate(0.44 g, 1.24 mmol) in dichloromethane (4 mL) was added triethylsilane(1.10 mL, 6.22 mmol) under nitrogen. The mixture was cooled to −30° C.then trifluoroacetic acid (0.48 mL, 6.22 mmol) added dropwise,maintaining the temperature below −25° C. After 2.5 h, the reactionmixture was allowed to warm to 0° C. and additional trifluoroacetic acid(0.48 mL, 6.22 mmol) added over 5 min. The reaction mixture was allowedto warm to room temperature and left to stir for 3 days. Ice was thenadded to the reaction mixture, followed by potassium hydroxide to a pHof 14, and the resultant slurry extracted with dichloromethane. Thecombined organic extracts were dried (Na₂SO₄) and concentrated in vacuoto yield a yellow oil. The oil was dissolved in methanol and loaded ontoan SCX-2 column. The column was washed with methanol, then a 2N solutionof ammonia in methanol. Concentration in vacuo of the ammonia solutionyielded 4-(1,2-dihydro-5-acenaphthylenyl)piperidine as a pale yellowoil.

c)(1S)-1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)-1-piperidinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide

4-(1,2-Dihydro-5-acenaphthylenyl)piperidine was coupled with2-[(1S)-6-aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate, as described for Example 1b), to yield(1S)-1-{2-[4-(1,2-dihydro-5-acenaphthylenyl)-1-piperidinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamideas a pale yellow oil. M+H=441.

EXAMPLE 10(1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-1,3-dihydro-2-benzofuran-5-carboxamide

a) 5-Chloro-1,3-dihydro-2-benzofuran-1-ol

To a solution of 5-chlorophthalide (3.64 g, 21.6 mmol) indichloromethane (100 mL) at −78° C. was added di-isobutylaluminiumhydride (1M in toluene) (23.8 mL, 23.8 mmol) dropwise. After 1 h thereaction mixture was quenched with a saturated solution of sodiumtartrate (250 mL), allowed to warm to room temperature and stirred for 1h. The layers were separated and the aqueous layer extracted withdichloromethane. The combined organic layers were dried (MgSO₄),filtered and concentrated in vacuo to yield the title compound as awhite solid.

b) Ethyl (5-chloro-1,3-dihydro-2-benzofuran-1-yl)acetate

5-Chloro-1,3-dihydro-2-benzofuran-1-ol (2.95 g, 17.3 mmol) was dissolvedin THF (60 mL) and cooled to 0° C. Triethyl phosphonoacetate (11.7 g,52.1 mmol) and caesium carbonate (17 g, 52.1 mmol) were added. After 20min the cold bath was removed and the reaction mixture allowed to stirat room temperature for 3 h, then quenched with a saturated solution ofammonium chloride and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried (MgSO₄), filtered and evaporated invacuo. Purification by column chromatography, eluting with ethylacetate/hexane (1:4), yielded the title compound as a colourless oil.

c) 2-(5-Chloro-1,3-dihydro-2-benzofuran-1-yl)ethanol

Ethyl (5-chloro-1,3-dihydro-2-benzofuran-1-yl)-acetate (2.79 g, 11.6mmol) in THF (60 mL) was cooled to −78° C. and di-isobutylaluminiumhydride (1M in toluene) (12.7 mL, 12.7 mmol) was added dropwise. After 1h, the reaction mixture was quenched with a saturated solution of sodiumtartrate (150 mL), allowed to warm to room temperature and stirred for 1h. The layers were separated and the aqueous layer extracted with ethylacetate. The combined organic layers were dried (MgSO₄), filtered andevaporated in vacuo. The resultant crude intermediate was dissolved inmethanol (50 mL), cooled to 0° C., and sodium borohydride (0.48 g, 12.7mmol) added in portions. The reaction was quenched with saturated sodiumhydrogen carbonate and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried (MgSO₄), filtered andevaporated in vacuo. The crude product was purified by columnchromatography, eluting with ethyl acetate/hexane (1:2), to yield thetitle compound as a white solid.

d)tert-Butyl-[2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)ethoxy]dimethylsilane

Prepared from 2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)ethanol, asdescribed for the preparation of2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyltert-butyl(dimethyl)silyl ether, to yieldtert-butyl-[2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)ethoxy]-dimethylsilane.

e)1-[2-(tert-Butyldimethylsilanoxy)-ethyl]-1,3-dihydro-2-benzofuran-5-carboxamide

A solution oftert-butyl-[2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)-ethoxy]dimethylsilane(0.94 g, 1.48 mmol) in dioxan (2 mL) and a solution oftri-tert-butylphosphine (89 mg, 0.44 mmol) in dioxan (0.7 mL) were addeddropwise to a round bottom flask charged withtris(dibenzylideneacetone)dipalladium (136 mg, 0.148 mmol) and zinccyanide (0.208 g, 1.78 mmol). The flask was fitted with a refluxcondenser and the resulting red-purple suspension heated at 120° C.under nitrogen. After 16 h the reaction mixture was cooled to roomtemperature and diluted with ethyl acetate, filtered through a pad ofcelite and concentrated in vacuo. The crude product was purified bychromatography on silica, eluting with hexane/ethyl acetate (10:1), toyield the title compound contaminated with dibenzylideneacetone. Thiscrude mixture was dissolved in dichloromethane (3 mL), andtetrabutylammonium hydrogen sulfate (0.29 mmol) was added in oneportion. Hydrogen peroxide (30% w/v aqueous solution) (5.75 mmol) andsodium hydroxide (2N aqueous solution) (1.15 mL, 2.3 mmol) were addeddropwise. The resulting reaction mixture was sonicated for 1 h, thenquenched with potassium hydrogen sulfate (4 mL), diluted withdichloromethane, and the layers separated. The organic layer was washedwith an aqueous solution of sodium sulfite, dried (MgSO₄), filtered andevaporated in vacuo. The crude product was purified by chromatography onsilica, eluting with ethyl acetate/hexane (1:1), to yield the titlecompound as a white solid.

f) 1-(2-Hydroxyethyl)-1,3-dihydro-2-benzofuran-5-carboxamide

Prepared from1-[2-(tert-butyldimethylsilanoxy)-ethyl]-1,3-dihydro-2-benzofuran-5-carboxamide,as described for the preparation of(1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide.

g)(1S)1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-1,3-dihydro-2-benzofuran-5-carboxamide

The title compound was prepared from1-(2-hydroxyethyl)-1,3-dihydro-2-benzofuran-5-carboxamide by initialformation of the methanesulfonate as described for the preparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate, and condensation of this sulfonate with(3R)-1-(1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine, as describedfor Example 1b). The mixture of diastereomers was separated by chiralHPLC using a Chiracel OJ column, eluting with hexane/ethanol (1:1) with0.2% dimethylethylamine. M+H=442.

EXAMPLE 111-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-1H-1,4-diazepin-1-yl]ethyl}-1,3-dihydro-2-benzofuran-5-carboxamide

a) (−)-(5-Chloro-1,3-dihydro-2-benzofuran-1-yl)acetic acid

(±/−)-Ethyl (5-chloro-1,3-dihydro-2-benzofuran-1-yl)acetate (6.1 g, 25.3mmol) and Amano Lipase P30 (3.8 g) were suspended in pH 7.0 buffersolution (150 mL) and the mixture was vigorously stirred for 24 h. Thesuspension was then filtered through a pad of celite, and the filter padwashed with water, hydrochloric acid (1M) and several times with ethylacetate. The aqueous layer was separated and washed twice with ethylacetate. The combined organic phase was then extracted with saturatedaqueous sodium bicarbonate (3×150 mL), dried over magnesium sulphate,filtered and evaporated under reduced pressure to give a pale yellowoil, (+)-ethyl(5-chloro-1,3-dihydro-2-benzofuran-1-yl)acetate (95% ee bychiral HPLC)—this could be recycled by base catalysed racemisation, asdescribed below.

The aqueous bicarbonate layer was then acidified with hydrochloric acid(1N), extracted with dichloromethane (3×), dried (MgSO₄), filtered andevaporated in vacuo to give a white crystalline solid. (95% ee by chiralHPLC). The solid was recrystallized from hexane-ether to provide thetitle acid (>98% ee).

b) (−)-2-(5-Chloro-1,3-dihydro-2-benzofuran-1-yl)ethanol

(5-Chloro-1,3-dihydro-2-benzofuran-1-yl)acetic acid (1.91 g, 9.0 mmol)was dissolved in dry THF (8 mL) under nitrogen and cooled to 0° C.Borane-dimethylsulfide complex (0.155 mL, 1.64 mmol) was added bysyringe. After 1 h the cooling bath was removed and the solution wasstirred at room temperature for 2 h. The solution was partitionedbetween saturated aqueous sodium hydrogen carbonate and diethyl ether.The aqueous layer was further extracted with ether, and the combinedorganic layers washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. This yielded the title compound as a white solid(>98% ee by chiral HPLC).

c) (±)-Ethyl (5-chloro-1,3-dihydro-2-benzofuran-1-yl)acetate

(+)-Ethyl (5-chloro-1,3-dihydro-2-benzofuran-1-yl)acetate (95% ee) (185mg, 0.77 mmol) was dissolved in dry ethanol (8 mL) under nitrogen.Sodium ethoxide (5 mg, 0.07 mmol) was added in one portion and thereaction stirred at room temperature overnight. The solvent was removedin vacuo and the residue partitioned between water and dichloromethane.The organic layer was washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo to provide the title compound as a yellow oil.

d) (−)-2-[(5-Aminocarbonyl)-1,3-dihydro-2-benzofuran-1-yl]ethylmethanesulfonate

Prepared from (−)-2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)ethanol, asdescribed in Example 10 with the corresponding racemic alcohol.

e)(−)-1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-1H-1,4-diazepin-1-yl]ethyl}-1,3-dihydro-2-benzofuran-5-carboxamide

Prepared from1-(1,2-dihydro-5-acenaphthylenyl)-hexahydro-1H-1,4-diazepine and(−)-2-[(5-aminocarbonyl)-1,3-dihydro-2-benzofuran-1-yl]ethylmethanesulfonate, as described for Example 8. M+H=442.

EXAMPLE 121-({2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methanamine

a) 1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile

2-(6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (1.3 g, 5.1 mmol),zinc cyanide (0.36 g, 3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) were stirred in degassed DMF (20 mL) undernitrogen at reflux for 9 h. The reaction mixture was diluted withtoluene and washed with 2M aqueous ammonia, the aqueous layer furtherextracted with ethyl acetate, then the combined organic extracts washedwith brine. The organic extracts were dried (MgSO₄), filtered andevaporated in vacuo. Purification by flash chromatography on silica,eluting with ethyl acetate/hexane (30:70 to 0:100), yielded the titlecompound as a light brown oil.

b) 2-(6-Cyano-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonate

Prepared from1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile, asdescribed for the preparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate.

c)1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carbonitrile

Prepared by condensation of2-(6-cyano-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonate with(3R)-1-(6-Fluoro-1-naphthyl)-3-methylpiperazine, as described forExample 1b).

d)1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methanamine

To a stirred solution of1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carbonitrile(0.50 g, 1.2 mmol) in dry THF (4 mL) was added lithium aluminium hydride(1M solution in THF) (1.4 mL, 1.4 mmol) and the mixture stirredovernight at room temperature. The reaction was quenched by cautiousaddition of 2M sodium hydroxide, then extracted into chloroform. Thecombined organic extracts were dried (MgSO₄), filtered and evaporated invacuo. The crude product was purified by preparative LC-MS to yield thetitle compound as a yellow oil. M+H=480.

EXAMPLE 131-({2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methylformamide

To a stirred solution of1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methanamine(0.234 g, 0.53 mmol) in dry DMF (10 mL) was added formic acid (27 mg,0.59 mmol), and the reaction mixture heated at reflux for 1 h undernitrogen. The mixture was diluted with dichloromethane and washed threetimes with water, then aqueous sodium hydrogen carbonate, dried (MgSO₄),filtered and evaporated in vacuo. The crude product was purified bypreparative LC-MS to yield the title compound as a beige solid. M+H=508.

EXAMPLE 14N-[((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]acetamide

a) 1-(2-Oxoethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile

Dimethylsulfoxide (0.35 mL, 5 mmol) and oxalyl chloride (2M indichloromethane) (2.2 mL, 4.4 mmol) were stirred in dichloromethane (30mL) under nitrogen at −78° C. After 10 min,1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (0.48 g,2.4 mmol) in dichloromethane (50 mL) was added dropwise and the solutionstirred at −78° C. for 1 h, before triethylamine (2.5 mL, 18 mmol) wasadded slowly. The reaction was allowed to warm to room temperature andafter 2 h the reaction was quenched by addition of water. Removal of thesolvent in vacuo yielded the title compound, which was used in the nextstep without further purification.

b)1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carbonitrile

To a stirred solution of1-(2-oxoethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (0.454 g, 2.26mmol) in methanol (30 mL) was added(3R)-1-(6-fluoro-1-naphthyl)-3-methylpiperazine (0.61 g, 2.49 mmol), andthe mixture stirred for 10 min. Sodium cyanoborohydride (0.157 g, 2.49mmol) and acetic acid (0.25 mL) were added and the mixture stirred for18 h. A further portion of sodium cyanoborohydride (0.20 g) was addedand the reaction stirred for 6 h. The mixture was quenched with water,and the solvent removed in vacuo. Water was added and the mixtureextracted with chloroform, the organic extracts dried (MgSO₄), filteredand evaporated in vacuo. The crude product was purified by preparativeLC-MS to yield the title compound as a yellow oil.

c)1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methanamine

1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carbonitrilewas reduced with lithium aluminium hydride, as described for Example12d).

d)N-[((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]acetamide

To a solution of1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methanamine(0.11 g, 0.25 mmol) in dry dichloromethane (10 mL) under nitrogen wasadded triethylamine (0.3 mL), then acetyl chloride (0.5 mL, 0.5 mmol),and the mixture stirred at room temperature for 1 h. The reaction wasquenched with water and the organic layer dried (MgSO₄), filtered andevaporated in vacuo. The crude product was purified by preparative LC-MSto yield the title compound as a white solid. M+H=522.

EXAMPLE 15N-[((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]methanesulfonamide

1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methanaminewas acylated with methanesulfonyl chloride as described for Example14d), to yield the title compound. M+H=512.

EXAMPLE 165-[(3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl)piperazinyl]-2-naphthonitrile

a) 2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyltert-butyl(diphenyl)silyl ether

To a solution of2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (3.0 g, 11.7mmol) in dry THF (100 mL) was added imidazole (3.97 g, 58.4 mmol) andchloro-tert-butyl(diphenyl)silane (6.42 g, 23.4 mmol), and the mixturestirred under nitrogen at room temperature for 20 h. Diethyl ether wasadded and the mixture filtered through a pad of silica. The filtrate wasevaporated in vacuo and the crude product purified by flashchromatography on silica, eluting with ethyl acetate/heptane (0:10 to2:8), to yield the title compound.

b)(1S)-1-(2-{[tert-Butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-carbaldehyde

To a stirred solution of2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyltert-butyl(diphenyl)silyl ether (2.5 g, 5.05 mmol) in dry THF (60 mL),cooled to −78° C. under nitrogen, was slowly added n-butyllithium (2.5Min THF) (5.4 mL, 13.5 mmol). After 30 min stirring at −78° C., drydimethylformamide (3.5 mL, 45 mmol) was added and the reaction allowedto warm to room temperature overnight. The reaction was quenched byaddition of water and extracted into ethyl acetate. The combined organicextracts were washed with brine, dried (MgSO₄), filtered and evaporatedin vacuo. The resultant yellow oil was purified by flash chromatographyon silica, eluting with ethyl acetate/hexane (0:4 to 1:3), to yield thetitle compound as a colourless oil.

c)[(1S)-1-(2-{[tert-Butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methanol

To a stirred solution of(1S)-1-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-carbaldehyde(0.97 g, 2.18 mmol) in ethanol (30 mL) was added sodium borohydride(0.116 g, 3.06 mmol) and the mixture stirred for 1.5 h at roomtemperature. The reaction was extracted from water into ethyl acetate,the combined organic extracts dried (MgSO₄), filtered and evaporated invacuo, to yield the title compound as a colourless oil.

d)3-{[(1S)-1-(2-{[tert-Butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methyl}-1,3-oxazolidin-2-one

To a stirred solution of[(1S)-1-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methanol(0.30 g, 0.67 mmol) in dry diethyl ether (5 mL) and triethylamine (0.11mL, 0.80 mmol) was added methanesulfonyl chloride (0.057 mL, 0.74 mmol),and the mixture stirred for 2 h under nitrogen. In a separate flask,sodium hydride (60% suspension in oil) (0.107 g, 2.68 mmol) was added toa stirred solution of 1,3-oxazolidin-2-one (0.175 g, 2.1 mmol) and themixture heated at 50° C. for 2 h. To this solution was added thefiltered solution of the mesylate and the mixture heated at 50° C. withstirring for a further 1.5 h, then stirred at room temperatureovernight. Ethyl acetate and water were added to the reaction, theorganic layer washed with brine, dried (MgSO₄), filtered and evaporatedin vacuo. The crude product was purified by flash chromatography onsilica, eluting with ethyl acetate/hexane (1:99 to 60:40), to yield thetitle compound.

e)3-{[(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methyl}-1,3-oxazolidin-2-one

To a stirred solution of3-{[(1S)-1-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methyl}-1,3-oxazolidin-2-one(0.22 g, 0.43 mmol) in dry THF (30 ml) was added tetrabutylammoniumfluoride (1M solution in THF) (0.51 mL, 0.51 mmol) and the reactionstirred at room temperature under nitrogen over the weekend. Thereaction was quenched by addition of water and extracted withdichloromethane. The combined organic extracts were dried (MgSO₄),filtered and evaporated in vacuo. The crude product was purified byflash chromatography on silica, eluting with methanol/dichloromethane(1:9), to yield the title compound as a colourless oil.

f)5-[(3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl)piperazinyl]-2-naphthonitrile

3-{[(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methyl}-1,3-oxazolidin-2-onewas reacted with methanesulfonyl chloride, as described for thepreparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate. The resultant crude mesylate was then condensed with(3R)-1-(6-cyano-1-naphthyl)-3-methylpiperazine, as described for Example1b), to yield the title compound. M+H=511.

The following Examples were similarly prepared, replacing the1,3-oxazolidin-2-one in Example 16d) with the appropriate heterocycleand increasing the reaction time with the mesylate from 1.5 h to 3 h at50° C.:

EXAMPLE 173-[((1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]-1,3-oxazolidin-2-one

Prepared from 1,3-oxazolidin-2-one. M+H=512.

EXAMPLE 183-[(3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-1,3-oxazolidin-3-yl)methyl]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl)-piperazinyl]-1-benzothiophene-6-carbonitrile

Prepared from 1,3-oxazolidin-2-one. M+H=517.

EXAMPLE 191-[((1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)methyl]-2-pyrrolidinone

Prepared from 2-pyrrolidinone. M+H=510.

EXAMPLE 203-[(3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-1-pyrrolidinyl)methyl]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl)piperazinyl]-1-benzothiophene-6-carbonitrile

Prepared from 2-pyrrolidinone. M+H=515.

EXAMPLE 21(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(1S)-6-(1H-imidazol-1-ylmethyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-2-methylpiperazine

Prepared from imidazole. M+H=493.

EXAMPLE 223-((3R)-4-{2-[(1S)-6-(1H-Imidazol-1-ylmethyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-3-methyl-piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared from imidazole. M+H=498.

EXAMPLE 233-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-pyrazol-1-ylmethyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared from pyrazole. M+H=498.

EXAMPLE 24(1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine

a)(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-N-(diphenylmethylene)-3,4-dihydro-1H-2-benzopyran-6-amine

{2-[(1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl]ethoxy}(tert-butyl)dimethylsilane(1.86 g, mmol) was dissolved in dry toluene (25 mL),tris(dibenzylideneacetone)dipalladium (0.234 g, mmol) added and themixture degassed by alternate evacuation and flushing with nitrogen.BINAP (0.495 g, mmol), sodium tert-butoxide (0.769 g, mmol) andbenzophenone imine (1 mL) were added with stirring and the reactionheated at 90° C. under nitrogen for 18 h. The mixture was cooled,diluted with diethyl ether and filtered through celite. The crudeproduct was evaporated in vacuo and used in the next step withoutfurther purification.

b)2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethanol

(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-N-(diphenylmethylene)-3,4-dihydro-1H-2-benzopyran-6-aminewas deprotected with aqueous acetic acid, as described for thepreparation of(1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide, toyield2-{(1S)-6-[(diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethanol.

c)2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethylmethanesulfonate

2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethanolwas reacted with methanesulfonyl chloride, as described for thepreparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate, to yield2-{(1S)-6-[(diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethylmethanesulfonate.

d)(1S)-N-(Diphenylmethylene)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine

2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethylmethanesulfonate was coupled with(3R)-1-(6-fluoro-1-naphthyl)-3-methylpiperazine, as described forExample 1b), to yield(1S)-N-(diphenylmethylene)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine.

e)(1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine

To a solution of(1S)-N-(diphenylmethylene)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]-ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine(1.46 g, 2.5 mmol) in methanol (25 mL) was added sodium acetate (0.28 g,2.65 mmol) and hydroxylamine hydrochloride (0.194 g, 2.8 mmol), and themixture stirred at room temperature under nitrogen for 18 h. Water wasadded and extracted with dichloromethane. The combined organic extractswere dried (MgSO₄), filtered and evaporated in vacuo. The crude productwas purified by flash chromatography on silica, eluting withmethanol/ethyl acetate (0:100 to 15:85), to yield(1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine.M+H=420.

The following amines were similarly prepared from2-{(1S)-6-[(diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethylmethanesulfonate and the appropriate aryl piperazine, and subsequentlyfurther. derivativatised as described below:

-   (1S)-1-{2-[(2R)-4-(6-Cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine-   (1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine-   (1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine

EXAMPLE 253-((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one

To a solution of(1S)-1-{2-[(2S)-4-(6-fluoro-1-naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine(0.217 g, mmol) in dry DMF (5 mL) was added pyridine (0.05 mL, mmol) and2-chloroethyl chloroformate (0.055 mL, mmol), and the reaction stirredat room temperature under nitrogen for 2 h. The reaction was quenched byaddition of 2M sodium hydroxide (3 mL), diluted with water and extractedinto dichloromethane. The combined organic extracts were dried (MgSO₄),filtered and evaporated in vacuo. The crude product was purified by prepLCMS to yield3-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]-ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one.M+H=490.

EXAMPLE 263-((1S)-1-{2-[(2R)-4-(6-Cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one

Prepared from(1S)-1-{2-[(2R)-4-(6-cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine,as described for Example 25. M+H=497.

EXAMPLE 273-((1S)-1-{2-[(2R)-4-(1,2-dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one

Prepared from(1S)-1-{2-[(2R)-4-(1,2-dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine,as described for Example 25. M+H=498.

EXAMPLE 283-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one

Prepared from(1S)-1-{2-[(2R)-4-(6-cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine,as described for Example 25. M+H=503.

EXAMPLE 291-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-pyrrolidinone

The title compound was prepared as described for Example 25,substituting 4-bromobutyryl chloride for 2-chloroethyl chloroformate.M+H=488.

EXAMPLE 301-((1S)-1-{2-[(2R)-4-(6-Cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-pyrrolidinone

Prepared from(1S)-1-{2-[(2R)-4-(6-cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine,as described for Example 29. M+H=495.

EXAMPLE 311-((1S)-1-{2-[(2R)-4-(6-cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-pyrrolidinone

Prepared from(1S)-1-{2-[(2R)-4-(6-cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine,as described for Example 29. M+H=501.

EXAMPLE 321-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-azetidinone

The title compound was prepared as described for Example 25,substituting 3-brompropionyl chloride for 2-chloroethyl chloroformateand maintaining the reaction for 3 days. M+H=474.

EXAMPLE 331-((1S)-1-{2-[(2R)-4-(6-cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-azetidinone

Prepared from(1S)-1-{2-[(2R)-4-(6-cyano-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine,as described for Example 32. M+H=481.

EXAMPLE 34(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(1S)-6-(1,1-dioxido-2-isothiazolidinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-2-methylpiperazine

a)N-[(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]-3-chloro-1-propanesulfonamide

To a stirred solution of(1S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-amine(0.15 g, 0.49 mmol) in ethyl acetate (18 mL), cooled to 0° C., was addedtriethylamine (0.274 mL, 1.37 mmol) then 3-chloro-1-propanesulfonylchloride (0.070 mL, 0.576 mmol), and the reaction mixture allowed towarm to room temperature. After stirring for 1 h, the reaction wasbasified with 1N sodium hydroxide (2.5 mL), and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(MgSO₄), filtered and evaporated in vacuo to yield the title compound asan oil. This crude product was used in the next step without furtherpurification.

b)2-[(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]isothiazolidine1,1-dioxide

To a stirred solution ofN-[(1S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]-3-chloro-1-propanesulfonamide(0.367 g, 0.82 mmol) in DMF (8 mL), cooled to 0° C., was added sodiumhydride (60% dispersion in oil) (0.036 g, 0.9 mmol) and the mixtureallowed to warm to room temperature. After 30 min, the reaction wasquenched by addition of water and extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried (MgSO₄),filtered and evaporated in vacuo. The title compound, as an oil, wasused in the next step without further purification.

c)2-[(1S)-6-(1,1-Dioxido-2-isothiazolidinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol

Prepared from2-[(1S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]isothiazolidine1,1-dioxide, as described for the preparation of(1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide.

d)(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(1S)-6-(1,1-dioxido-2-isothiazolidinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-2-methylpiperazine

2-[(1S)-6-(1,1-Dioxido-2-isothiazolidinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanolwas reacted with methanesulfonyl chloride, as described for thepreparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate. The resultant crude mesylate was then condensed with(3R)-1-(1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine, as describedfor Example 1b), to yield the title compound. M+H=532.

EXAMPLE 351-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-imidazolidinoneMethod A

a) 2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethylmethanesulfonate

The title compound was prepared from2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol andmethanesulfonyl chloride, as described for the preparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate.

b)3-((3R)-4-{2-[(1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-3-methylpiperazinyl)-1-benzothiophene-6-carbonitrile

The title compound was prepared from2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonateand (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as describedfor Example 1b).

c)1-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-imidazolidinone

3-((3R)-4-{2-[(1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-3-methylpiperazinyl)-1-benzothiophene-6-carbonitrile(0.36 g, 0.73 mmol)was dissolved in dry toluene (15 mL) and degassed.2-Imidazolidinone (0.071 g, 0.82 mmol),tris(dibenzylideneacetone)dipalladium (34 mg),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (47 mg) and caesiumcarbonate (0.34 g, 1.05 mmol)were added and the mixture heated underreflux with stirring, under a nitrogen atmosphere, for 2 days. Thereaction was cooled to room temperature, diluted with dichloromethane,filtered through celite and washed with water. The organic extracts weredried (MgSO₄), filtered and evaporated in vacuo. Purification by LC-MSyielded the title compound as the free base. M+H=502.

Method B

a)3-[(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]-1,3-oxazolidin-2-one

To a stirred solution of2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (0.815 g, 3.17mmol) in dry dioxan (5 mL) was added 1,3-oxazolidin-2-one (0.26 g, 2.95mmol), trans-1,2-cyclohexanediamine (0.05 mL, 0.42 mmol), copper(I)iodide (0.040 g, 0.21 mmol) and potassium carbonate (1.02 g, 7.36 mmol),and the mixture heated at reflux under nitrogen overnight. 2M Ammoniawas added and the mixture extracted into dichloromethane. The combinedorganic extracts were dried (MgSO₄), filtered and evaporated in vacuo.The crude product was purified by flash chromatography on silica toyield the title compound.

b)2-((1S)-6-(2-Oxo-imidazolidin-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl)ethylmethanesulfonate

Prepared from3-[(1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]-1,3-oxazolidin-2-oneand methanesulfonyl chloride, as described for the preparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate

c)1-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-imidazolidinone

The title compound was prepared by condensation of2-((1S)-6-(2-oxo-imidazolidin-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl)ethylmethanesulfonate and(3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as described forExample 1b). M+H=502.

EXAMPLE 361-((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2-imidazolidinone

Prepared from (3R)-1-(6-cyano-1-naphthyl)-3-methylpiperazine, asdescribed for Example 35, Method A. M+H=489.

EXAMPLE 371-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-3-methyl-2-imidazolidinone

Prepared as described for Example 35, Method B, substituting1-methyl-2-imidazolidinone for 2-imidazolidinone. M+H=516.

EXAMPLE 383-((3R)-3-Methyl-4-{2-[(1S)-6-(4-thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

a)2-[(1S)-6-(4-Thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol

2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (0.26 g, 0.99mmol) was dissolved in dry toluene (10 mL) and degassed. Thiomorpholine(0.14 mL, 1.48 mmol), tris(dibenzylideneacetone)dipalladium (51 mg),(+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (77 mg) and sodiumtert-butoxide (0.126 g, 1.3 mmol) were added and the mixture heatedunder reflux with stirring, under a nitrogen atmosphere, for 24 h. Thereaction was cooled to room temperature, diluted with dichloromethane,filtered through celite and washed with water. The organic extracts weredried (MgSO₄), filtered and evaporated in vacuo. The crude product waspurified by flash chromatography on silica, to yield the title compound.

b) 2-[(1S)-6-(4-Thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate

Prepared from2-[(1S)-6-(4-thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanoland methanesulfonyl chloride, as described for the preparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate.

c)3-((3R)-3-Methyl-4-{2-[(1S)-6-(4-thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared by condensation of2-[(1S)-6-(4-thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate with(3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as described forExample 1b). M+H=519.

EXAMPLE 393-((3R)-3-Methyl-4-{2-[(1S)-6-(4-morpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared as described for Example 38, substituting thiomorpholine withmorpholine. M+H=503.

EXAMPLE 40(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine

a) 2-[(1S)-6-(1H-Pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol

2-((1S)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (0.54 g, 2.1mmol), pyrazole (0.29 g, 4.3 mmol), copper(I) iodide (0.062 g, 0.33mmol) and potassium carbonate (0.30 g, 2.2 mmol) were stirred in dry DMF(3 mL) under nitrogen and heated at 150° C. for 18 h. The reactionmixture was cooled and extracted from water into dichloromethane. Thecombined organic extracts were dried (MgSO₄), filtered and evaporated invacuo. The crude product was used in the next step without furtherpurification.

b) 2-[(1S)-6-(1H-Pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate

Prepared from2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol andmethanesulfonyl chloride, as described for the preparation of2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate.

c)(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine

Prepared by condensation of2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethylmethanesulfonate with(3R)-1-(1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine, as describedfor Example 1b). M+H=479.

The following Examples were similarly prepared, reacting2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol with theappropriate heterocycle, then condensation of the subsequent mesylatewith the appropriate aryl piperazine:

EXAMPLE 413-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared from pyrazole. M+H=484.

EXAMPLE 42(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(1S)-6-(1H-imidazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-2-methylpiperazine

Prepared from imidazole. M+H=479.

EXAMPLE 433-((3R)-4-{2-[(1S)-6-(1H-Imidazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}-3-methylpiperazinyl)-1-benzothiophene-6-carbonitrile

Prepared from imidazole. M+H=484.

EXAMPLE 44(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine

Prepared from 1,2,3-triazole, to give a mixture with the6-(triazol-1-yl)benzopyran, which was separated by preparative LC-MS.M+H=480.

EXAMPLE 45(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(1H-1,2,3-triazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine

Prepared from 1,2,3-triazole, to give a mixture with the6-(triazol-2-yl)benzopyran, which was separated by preparative LC-MS.M+H=480.

EXAMPLE 463-((3R)-3-Methyl-4-{2-[(1S)-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared from 1,2,3-triazole, to give a mixture with the6-(triazol-1-yl)benzopyran, which was separated by preparative LC-MS.M+H=485.

EXAMPLE 473-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-1,2,3-triazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared from 1,2,3-triazole, to give a mixture with the6-(triazol-2-yl)benzopyran, which was separated by preparative LC-MS.M+H=485.

EXAMPLE 48(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-[(1S)-6-(1H-1,2,4-triazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazine

Prepared from 1,2,4-triazole. M+H=480.

EXAMPLE 493-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-1,2,4-triazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared from 1,2,4-triazole. M+H=485.

EXAMPLE 501-((1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-2(1H)-pyridinone

Prepared from 2-hydroxypyridine. M+H=506.

EXAMPLE 513-((3R)-3-Methyl-4-{2-[(1S)-6-(2-oxo-1(2H)-pyridinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-benzothiophene-6-carbonitrile

Prepared from 2-hydroxypyridine. M+H=511.

1. A compound of the formula

in which R¹ is —CONR¹³R¹⁴ or —(CH₂)_(t)—R²¹, where R¹³ and R¹⁴ are eachhydrogen or C₁₋₆ alkyl, or R¹³ and R¹⁴ taken together with the nitrogenatom to which they are attached form a morpholino, pyrrolidino orpiperidinyl ring optionally substituted with one or two C₁₋₆ alkylgroups; —R²¹ is

where R¹³, R¹⁴, R²² and R²³ are each hydrogen or C₁₋₆ alkyl, or R¹³ andR¹⁴ taken together with the nitrogen atom to which they are attachedform a morpholino, pyrrolidino or piperidinyl ring optionallysubstituted with one or two C₁₋₆ alkyl groups; R²⁴ is selected fromhydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, carboxy, hydroxy, cyano, halo,trifluoromethyl, nitro, amino, C₁₋₆ acylamino, C₁₋₆ alkylthio, phenyl orphenoxy; R² is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or halo; R³, R⁴, R⁵,R⁶, R⁷, and R⁸ are each hydrogen or C₁₋₆ alkyl; R⁹, R¹⁰, R¹¹ and R¹² areeach hydrogen, C₁₋₆ alkyl or —(CH₂)_(q)—OR²⁰, wherein R²⁰ is C₁₋₆ alkyl;n is 1 or 2; p is 0, 1 or 2; t is 0, 1, or 2;

R²⁵ is hydrogen or C₁₋₆ alkyl; —X—Y— is

where Z is

in which -T- is —CH₂—, —O—, —S—, C(O)— or —CH═CH—, and m and s are each0 or 1; and R¹⁵ and R¹⁹ are each hydrogen, halo, C₁₋₆ alkyl or C₁₋₆alkoxy, carboxy-C₁₋₆ alkyl, cyano, halogen, trifluoromethyl,trifluoromethoxy, nitro, amino, C₁-C₆ acylamino or C₁-C₆ alkylthio; andprovided that when -T- is —CH₂—, —O—, —S— or —C(O)—, then (m+s) is 1 or2; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 wherein -T- is —CH₂— and (m+s) is 1, or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 1 wherein -T- is —CH═CH— and (m+s) is 0, or a pharmaceuticallyacceptable salt thereof.
 4. A compound according to claim 1 wherein -T-is —C(O)— and (m+s) is 1, or a pharmaceutically acceptable salt thereof.5. A compound according to claim 1 wherein -T- is —O—, m is 1 and s is1, or a pharmaceutically acceptable salt thereof.
 6. A compoundaccording to claim 1 wherein -T- is —S—, m is 1 and s is 1, or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 1 wherein R¹ is —(CH₂)_(t)—R²¹, or a pharmaceutically acceptablesalt thereof.
 8. A compound according to claim 7 wherein -T- is —CH₂—and (m+s) is 1, or a pharmaceutically acceptable salt thereof.
 9. Acompound according to claim 1 of the formula

wherein: R⁹ is C₁-C₆ alkyl and R¹⁰ is hydrogen; and —W— is —O—, or apharmaceutically acceptable salt thereof.
 10. A compound according toclaim 9 wherein R⁹ is C₁₋₆ alkyl and R¹⁰, R¹¹ and R¹² are hydrogen, or apharmaceutically acceptable salt thereof.
 11. The compound which is(1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamideor a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablediluent or carrier.
 13. A pharmaceutical composition comprising thecompound which is(1S-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamideor a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier.